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Vitamin D has immuno-modulatory properties, and deficient levels of circulating 25-hydroxyvitamin D (<30 nmol/l) may contribute to increased risk of infectious illnesses. This narrative review summarises data on vitamin D status in Europe and updates results of randomised controlled trials (RCTs) regarding vitamin D and airway infections such as tuberculosis (TB) and acute upper respiratory tract infection. In Europe, the prevalence of vitamin D deficiency is up to 37 % in the general population and up to 80 % in nursing home residents and non-European immigrants. Half of TB patients have a migration background. While results of RCTs do not support the concept of beneficial adjunctive effects of vitamin D supplements in anti-TB treatment [odds ratio (OR) = 0.86; 95 % CI 0.62–1.19], the few published RCTs on the prophylaxis of TB suggest some protective vitamin D effects in individuals with deficient circulating 25-hydroxyvitamin D levels. Regarding acute respiratory tract infection, RCTs indicate a significant risk reduction by vitamin D supplements [OR = 0.65; 95 % confidence interval (CI) 0.50–0.85]. There is evidence that daily administration is more effective than high-dose bolus administration [OR = 0.48 (95 % CI 0.30–0.77) vs. OR = 0.87 (95 % CI 0.67–1.14)] and that individuals with deficient or insufficient (30–50 nmol/l) circulating 25-hydroxyvitamin D levels benefit most. Several vitamin D effects on innate immunity may explain these protective effects. In summary, there is possible evidence from RCTs for protective vitamin D effects on TB and likely evidence for protective effects on acute airway infection. Since vitamin D deficiency is prevalent in Europe, especially in institutionalised individuals and non-European immigrants, daily oral vitamin D intake, e.g. 1000 international units, is an inexpensive measure to ensure adequate vitamin D status in individuals at risk.
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Zittermann et al. Eur J Med Res (2016) 21:14
DOI 10.1186/s40001-016-0208-y
REVIEW
Vitamin D andairway infections:
a European perspective
Armin Zittermann1*, Stefan Pilz2, Harald Hoffmann3 and Winfried März4,5,6
Abstract
Vitamin D has immuno-modulatory properties, and deficient levels of circulating 25-hydroxyvitamin D (<30 nmol/l)
may contribute to increased risk of infectious illnesses. This narrative review summarises data on vitamin D status in
Europe and updates results of randomised controlled trials (RCTs) regarding vitamin D and airway infections such as
tuberculosis (TB) and acute upper respiratory tract infection. In Europe, the prevalence of vitamin D deficiency is up
to 37 % in the general population and up to 80 % in nursing home residents and non-European immigrants. Half of
TB patients have a migration background. While results of RCTs do not support the concept of beneficial adjunctive
effects of vitamin D supplements in anti-TB treatment [odds ratio (OR) = 0.86; 95 % CI 0.62–1.19], the few published
RCTs on the prophylaxis of TB suggest some protective vitamin D effects in individuals with deficient circulating
25-hydroxyvitamin D levels. Regarding acute respiratory tract infection, RCTs indicate a significant risk reduction by
vitamin D supplements [OR = 0.65; 95 % confidence interval (CI) 0.50–0.85]. There is evidence that daily administra-
tion is more effective than high-dose bolus administration [OR = 0.48 (95 % CI 0.30–0.77) vs. OR = 0.87 (95 % CI
0.67–1.14)] and that individuals with deficient or insufficient (30–50 nmol/l) circulating 25-hydroxyvitamin D levels
benefit most. Several vitamin D effects on innate immunity may explain these protective effects. In summary, there is
possible evidence from RCTs for protective vitamin D effects on TB and likely evidence for protective effects on acute
airway infection. Since vitamin D deficiency is prevalent in Europe, especially in institutionalised individuals and non-
European immigrants, daily oral vitamin D intake, e.g. 1000 international units, is an inexpensive measure to ensure
adequate vitamin D status in individuals at risk.
Keywords: Vitamin D, 25-hydroxyvitamin D, Infection, Immune defence, Tuberculosis, Acute airway infection
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Background
Acute respiratory tract illnesses are very prevalent.
Most people will develop an infection every year. e
majority of these infections are caused by viruses, but
suppurative and non-suppurative bacterial complica-
tions are also possible [1]. Common cold and influenza
are frequent upper respiratory tract infections (URTIs)
[2]. Pneumonia is a lower respiratory tract infection,
which tends to be a far more serious condition than
URTIs, such as common cold [3]. Airway infections are
an important cause of disability, days lost from school or
work, hospitalisation and mortality [46]. In temperate
regions like Europe, there is strong seasonality of airway
infections, with peak levels being observed in the win-
ter [7]. Tuberculosis (TB), caused by the intracellular
pathogen M. tuberculosis (MTB), is an infection of the
lower respiratory tract. In approximately 80% of cases,
TB affects the lung, and in 20%, it affects any extrapul-
monary organ of the body including the skin. In Europe,
tuberculosis was widespread in the 19th and early 20th
centuries and was associated with high mortality rates
[8]. TB is still among the worldwide number one killers
among infectious diseases caused by single pathogens,
with more than 9m new cases and more than 1.5 m
deaths per year [9].
It has been assumed that vitamin D status may influ-
ence infectious diseases like TB and acute URTI (see
below). is assumption is based on findings that vita-
min D has important effects on the immune system (see
Open Access
European Journal
of Medical Research
*Correspondence: azittermann@hdz-nrw.de
1 Department of Thoracic and Cardiovascular Surgery, NRW Heart
and Diabetes Centre, Clinic for Thoracic and Cardiovascular Surgery, Ruhr
University of Bochum, Georgstraße 11, 32545 Bad Oeynhausen, Germany
Full list of author information is available at the end of the article
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Page 2 of 10
Zittermann et al. Eur J Med Res (2016) 21:14
below). is narrative review provides data on vitamin
D status in Europe, the history of TB treatment by vita-
min D in Europe, and updates results of randomised con-
trolled trials (RCTs) on vitamin D and airway infections
such as TB and acute URTI.
Vitamin D metabolism andstatus classication
Vitamin D has a special position among the vitamins
because the human body is able to synthesise it from
the precursor molecule 7-dehydrocholesterol (Fig. 1).
is is generated by the skin upon sufficient exposure
to solar ultraviolet radiation in wavelengths from 290 to
315nm (UVB radiation). Measurable quantities of vita-
min D also occur in some natural foods, in particular in
oily fish like eel, salmon and herring, as well as in cod
liver oil. Since its final effector molecule is produced in
the human organism, some authors consider vitamin
D more a pro-hormone than a vitamin sensu stricto
[10]. With modern lifestyles, however, the majority of
human beings worldwide stay indoors for most of the
time. is certainly leads to diminished or even absent
synthesis of vitamin D in the skin, in particular in certain
risk groups including office workers, nursing home resi-
dents, coloured populations living in northern latitudes
and women wearing traditional dresses which cover the
whole body. Due to increasing numbers of people fall-
ing into one of the aforementioned risk groups, it is very
likely that in future the vitamin nature of this essential
substance will become the focus of interest, i.e. the need
for its oral intake.
Vitamin D status is best determined by measuring
circulating 25-hydroxyvitamin D (25OHD) in plasma
or serum. 25OHD is the first hydroxylation product
of vitamin D and is synthesised in the liver. e North
American Institute of Medicine (IOM) has classified
serum 25OHD levels of 50 to 125nmol/l [20 to 50ng/
ml] as sufficient [1nmol/l=0.4ng/ml], levels between
30 and 49.99 [12and 19.99ng/ml] as inadequate, levels
below 30nmol/l [12ng/ml] as deficient and levels above
125nmol/l [50 ng/ml] as potentially harmful [11]. e
‘deficient’ and ‘inadequate’ categories have been set up
exclusively based on the effects of vitamin D on bone
health. e assumption of potentially harmful vitamin D
effects at levels above 125nmol/L originates from results
of prospective cohort studies of tumour incidence, myo-
cardial infarction and total mortality [11]. e Endocrine
Society (ES), in contrast, has set the lower threshold of
adequate 25OHD concentrations to 75 nmol/l (30 ng/
ml), i.e. 50% higher than the IOM [12]. e ES-recom-
mendation is not only based on convincing evidence of
positive vitamin D effects on the musculoskeletal system
but also on potential evidence of positive extra-skeletal
effects. e ES did not, however, define an upper thresh-
old of 25OHD levels.
e metabolically active form is 1,25-dihydroxyvitamin
D (1,25[OH]2D), which is produced from 25OHD mainly
in the kidney but also in different extra-renal tissues. e
human organism usually regulates serum concentration
of 1,25(OH)2D between quite strict limits. erefore,
1,25(OH)2D levels are clinically less meaningful. How-
ever, once the vitamin D supply becomes severely defi-
cient, the circulating 1,25(OH)2D level becomes substrate
dependent, i.e. dependent on circulating 25OHD levels,
and secondarily decreases as well [13].
To guarantee adequate vitamin D intake, the IOM rec-
ommends daily vitamin D intakes of 400, 600 and 800
international units (1IU=0.025µg) in the first year of
life, following infancy up to 70years of age, and beyond
70years of age, respectively. is corresponds well with
the recommendations of the German, Austrian and
Swiss Nutrition Society (D-A-CH) [11, 14]. IOM and
European Food Safety Authority have set 4000 IU as
the maximum permissible dose of safe daily vitamin D
intake.
Diet
UVB-Radiaon
Skin
Gut
7-Dehydro-
cholesterol
vitamin D
vitamin D
Liver
Kidneys
Extrarenal
Tissue
25-Hydroxyvitamin D
1-Hydroxylase 1-Hydroxylase
1,25-Dihydroxyvitamin D
25-Hydroxylase
Fig. 1 Simplified schematic vitamin D metabolism. Dietary vitamin D
and endogenously produced vitamin D are both first metabolised in
the liver into 25-hydroxyvitamin D and then in the kidney and various
extra-renal tissues into the vitamin D hormone
1,25-dihydroxyvitamin D
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Zittermann et al. Eur J Med Res (2016) 21:14
Literature review strategy andmethods
We performed a systematic literature search in Pub-
Med and Google Scholar without language restrictions
for relevant publications released until June 30th, 2015,
using the following terms: (“vitamin D” or “cholecalcif-
erol” or “25-hydroxyvitamin D”) and (“immune system”
or “infection” or “infectious disorder” “infectious disease”
or “immune defence” or “influenza” or “upper respira-
tory tract infection” or “tuberculosis” or “airway infec-
tion”). Personal collections of articles on this topic as
well as references from selected articles were also used
to extend the search. Some articles are not cited due to
space limitations. We systematically analysed retrieved
RCTs on vitamin D and tuberculosis/airway infection in
an approach similar to meta-analyses. We used RevMan
(Review Manager. Version 5.3.: e Nordic Cochrane
Centre. e Cochrane Collaboration. Copenhagen, 2014)
to perform the analyses.
Epidemiology ofvitamin D deciency inEurope
Circulating 25OHD levels can vary widely according to
lifestyles, skin pigmentation, dietary vitamin D intake,
season, latitude and health status. In the general adult
population of selected European countries (Austria,
Germany, United Kingdom, Denmark, Finland, Ireland
and Poland), the prevalence of vitamin D deficiency, e.g.
25OHD levels<25nmol/l, is 11.6–37% [15]. Moreover,
the HELENA (healthy lifestyle in Europe by nutrition in
adolescence) study has demonstrated that 15% of Euro-
pean adolescents have 25OHD levels<27.5 nmol/l [16].
is figure is similar to results of a representative Ger-
man survey in children and adolescents, where approxi-
mately 16% had 25OHD levels<25 nmol/l [17]. Usually,
peak levels of circulating 25OHD are achieved in sum-
mer, whereas a nadir is observed at the end of the winter.
Results from a recent retrospective survey with 98,000
patients tested between 2008 and 2011 in Northern
Germany support the season dependency of vitamin D
deficiency. Less than 10% and near to 40 % of partici-
pants had vitamin D deficiency during the summer and
the winter seasons, respectively [18]. In a nationwide
cohort of British adults at age 45years, the prevalence of
25OHD levels<25nmol/l was 3.2% in summer/autumn
and 15.5% in winter/spring [19]. at study also demon-
strated latitudinal differences in 25OHD levels, with 8%
higher prevalence of deficient 25OHD levels in Scotland
compared with the south of England. Data are in general
agreement with a French study reporting in middle-aged
men and women with a mean 25OHD level of 43nmol/l
in Northern France and 94nmol/l in the southwest of
France [20]. A particular risk group for vitamin D defi-
ciency is non-European immigrants. e aforementioned
German survey reported deficient 25OHD levels in up
to 30% of migrant girls, compared with 17% of native
German girls [17]. In the Netherlands and Denmark,
serum 25OHD was below 25nmol/l in up to 80% of non-
European immigrants, with particularly high prevalence
in girls and women [15]. Another particular risk group
for vitamin D deficiency is frail elderly people. In recent
studies from Germany and Austria [21, 22], the supply
situation was particularly poor in rehabilitation patients
and nursing home residents. 67 and 75 % had vitamin
D deficiency, respectively. In view of these devastating
vitamin D deficiency statistics, it should be taken into
consideration that the automated immunoassays meas-
uring 25OHD levels in blood may markedly vary, with
significant impact on vitamin D status classification [23].
In November 2010, an international collaborative ini-
tiative organised by the office of dietary supplements of
the National Institutes of Health therefore established
a vitamin D standardisation program (VDSP) [24]. A
recent study applied VDSP protocols to serum data from
representative childhood/teenage and adult/older adult
European populations [25]. An overall pooled estimate,
irrespective of age, showed that 13% of the 55,844 Euro-
pean individuals had yearly mean standardised serum
25OHD levels<30nmol/l. In Finnish and British immi-
grant groups, the prevalence was between 28 and 50%.
History oftreatment ofairway infection
Cod liver oil and UVB radiation, which today are known
to be the most effective sources of vitamin D for humans,
have long been used to treat airway infections such as
tuberculosis in Western Europe [26, 27]. In 1848, in one
of the very first clinical trials on the treatment of TB,
more than 1000TB patients were either assigned to the
verum group and received cod liver oil three times daily,
or to the control group with simple nursing care. 33% of
the control group versus 19% of the verum group expe-
rienced significant worsening of their disease or died
[26]. In 1903, Niels Finsen was awarded the Nobel Prize
in Physiology or Medicine for the proof that photother-
apy can cure lupus vulgaris (skin tuberculosis) [28]. In
the absence of effective antibiotics and chemotherapy,
heliotherapy (helios=sun) was quite popular in Western
Europe, exposing TB patients to UV rich sunlight in high
altitudes [27]. After the discovery of synthetic antitu-
berculous substances, starting with streptomycin in the
1940s, heliotherapy was displaced by the more effective
antituberculous chemotherapy [29]. In 2006, however, a
German-American working group demonstrated that
increased expression of the vitamin D receptor and of
the 1α-hydroxylase gene (the 1α-hydroxylase synthesises
25OHD) induces synthesis of the antimicrobial peptide
cathelicidin in human macrophages [30]. In the same
year, Cannell etal. [31] put forward the hypothesis that
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Zittermann et al. Eur J Med Res (2016) 21:14
vitamin D deficiency increases the risk of contracting
influenza in winter. Of note, during recent years, several
other natural products such as bacterial lysates or com-
ponents of bacterial cells (ribosomal extracts), prebiotic
oligosaccharides, probiotics and yeast-derived beta-glu-
cans have also been successfully used in airway infection
prevention [3235].
Clinical associations ofvitamin D withtuberculosis
Two effects have so far assigned to vitamin D with
regards to TB: (i) a potentially protective value of suf-
ficient vitamin D levels against reactivation of TB
infections and (ii) the therapeutic effect of vitamin D
supplementation on the clinical outcome of the active
disease. With respect to preventive vitamin D effects, it
is noteworthy that in European countries, approximately
half of TB patients have a migration background. Glob-
ally, the prevalence of TB per 100,000 people is highest
in sub-Saharan Africa and is also relatively high in Asia.
It has been argued that immigrants become infected in
their countries of origin and that the infection reacti-
vates upon enhanced vitamin D deficiency due to weaker
sunlight in the Northern regions [36]. So far, two RCTs
[37, 38] have investigated the protective effect of vita-
min D on TB. One trial [37] daily supplemented a verum
group of school children in the high TB incidence setting
of Mongolia with 800IU and compared the additional
numbers of latent TB infections measured with a tuber-
culin skin test with a placebo control group. e authors
found a strong protective trend in the verum group (risk
ratio: 0.41; 95 CI 0.16–1.09). Unfortunately, they did
not provide baseline data on smear-positive pulmonary
TB. e other trial [38] investigated the effect of a sin-
gle dose of 100,000IU vitamin D on adult persons who
had contact to TB index cases in the United Kingdom
(UK). e authors could not see a protective effect on the
risk of acquiring a latent TB infection as measured using
ESAT-6/CFP-10-based interferon-gamma release assays.
e authors observed, however, an enhanced antimicro-
bial invitro activity of blood from verum group patients
compared to controls against bacteria of a BCG vaccine
strain. But the clinical relevance of this finding could not
yet be established. Notably, in the Mongolian study, ini-
tial 25OHD levels were on average below 18nmol/l, and
thus in the range, the IOM has classified as deficient. In
the UK study, mean initial 25OHD levels were 35nmol/l
and thus slightly above the deficiency range.
Table 1 lists six published RCTs [3944] which have
examined the therapeutic effect of vitamin D on the
course of the disease. Four studies, one study and one
study were conducted in Asia, Africa, and the UK,
respectively. Different forms of pulmonary and extrapul-
monary TB were included in the studies. In five of the six
trials, high bolus doses of vitamin D were administered
once, on a weekly or on a monthly basis. One study only
had daily supplemented vitamin D at a dose of 10,000IU.
In two studies, 25OHD levels were not measured, and in
three other studies, initial 25OHD levels were on aver-
age already above 50nmol/l. Results of individual studies
and summary results are illustrated as odds ratios (ORs)
and 95% confidence intervals (CI) in Fig.2. Cases which
did not terminate the treatment according to the respec-
tive study protocols had to be excluded. Since there was
no evidence of heterogeneity in study results (I2=23%;
P=0.26), we used a fixed effects model. Overall, there
was a non-significant reduction of TB infections in the
vitamin D group (odds ratio: 0.86; 95 % CI 0.62–1.19;
P=0.338). Although in the study by Martineau [41] vita-
min D did not significantly affect time to sputum culture
conversion in the whole study population, it did signifi-
cantly hasten sputum culture conversion in participants
with the tt genotype of the TaqI vitamin D receptor poly-
morphism, indicating that vitamin D availability in target
cells may indeed influence disease outcome. e studies
were not designed to answer the question of whether
vitamin D was able to reduce mortality in TB patients.
Results would have been of scientific interest since ear-
lier systematic reviews and meta-analyses of RCTs had
already demonstrated that vitamin D supplements reduce
mortality from a variety of diseases [45, 46]. Interest-
ingly enough, several studies have also associated vitamin
D deficiency with other forms of lower respiratory tract
infections [4750].
Clinical associations ofvitamin D withacute airway
infections
Studies of the influence of vitamin D on URTIs are
methodically difficult because the duration and extent of
the infections are not always easy to record objectively.
Against this background, a Finnish study [51] stands out:
absence from duty due to respiratory tract infections was
studied in 800recruits, i.e. a homogeneous group of fun-
damentally healthy young men. It showed that recruits
with 25OHD concentrations of <40 nmol/l (16 ng/ml)
were unfit for work significantly more frequently than
recruits with higher 25OHD. Based on these data, a ran-
domised controlled extension trial, in which the recruits
received either 400IU of vitamin D or a placebo, was con-
ducted over the winter season (October to March) [52].
e mean duration of days of absence from duty tended
to be lower in the vitamin D group than in the placebo
group (on average 2.2 vs. 3.0days). Furthermore, the per-
centage of recruits with absence was significantly lower
than in the placebo group (35.7 vs. 51.3%). A meta-anal-
ysis of RCTs published by Bergman etal. [53] in 2013 sys-
tematically analysed the influence of vitamin D intake on
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Zittermann et al. Eur J Med Res (2016) 21:14
the risk of respiratory tract infection [53]. Included stud-
ies [52, 5463] are listed in Table2. Since publication of
this meta-analysis [53], several other RCTs [6468] have
been published on this topic and are presented in Table2,
resulting in 16 studies in total. Of these 16 studies, 11
were conducted in healthy subjects and five in patients,
the study participants being children in six studies and
adults in eleven studies. All 16 studies were included in
a new systematic analysis using a random effect model
(Fig.3). Outcome was the number of patients experienc-
ing at least one episode of infection. Overall, vitamin D
administration reduced the risk of infection significantly
(odds ratio=0.65; 95% CI 0.50–0.85; P=0.005). Exclu-
sion of the two studies by Manaseki-Holland etal. [56,
62] that used vitamin D to protect against a (repeat) epi-
sode of pneumonia did not change results substantially
(odds ratio=0.61; 95% CI 0.44–0.84; P<0.001). How-
ever, results showed significant heterogeneity among
studies (I2=74 %, P<0.001), supporting the need for
a random effects model. Subgroup analysis indicated
that daily vitamin D administration was associated with
a better outcome than (high-dose) bolus vitamin D
administration [odds ratio= 0.48 (95 % CI 0.30–0.77)
vs. odds ratio =0.87 (95 % CI 0.67–1.14)]. Moreover,
in three trials with initial 25OHD levels<50nmol/l [54,
60, 68], the odds ratio of vitamin D effectiveness was
0.55 (95% CI 0.20–1.55), indicating that initial 25OHD
level may also influence vitamin D effectiveness. Nota-
bly, Simpson etal. [67] reported that a protective vita-
min D effect could only be observed in the subgroup
of individuals with initial 25OHD levels <40 nmol/l. In
these individuals, vitamin D resulted in a 44% reduction
in infection risk (P=0.007). URTI and non-URTI were
included in this analysis. In the study by Rees etal. [64],
a further observational analysis of their data suggested
a significant decreased rate ratio of 0.91 (95% CI 0.83–
0.99) for URTI per 25nmol/l increase in 25OHD. A few
years ago, the analysis of an extensive US data set [69]
revealed, as expected, that URTI shows strong seasonal
variation, with the frequency peaking in winter. However,
people with deficient circulating 25OHD (<25 nmo/l
or<10ng/ml) always exhibited a higher risk than people
with adequate circulating 25OHD (>75nmol/l or>30ng/
ml).
Table 1 Randomised, controlled trials ofvitamin D fortreatment ofactive tuberculosis
25OHD 25-hydroxyvitamin D; IU international units; ND not determined
Author (ref.) Publication
year N
(total) Age
(years) Initial
25OHD (nmol/l) In-study
25OHD (nmol/l) Mean vitamin D
dose (IU) Duration Endpoint
Vit D Placebo Vit D Placebo
Nursyam [39] 2006 67 31 ND ND ND ND 10,000 daily 6 weeks Sputum conversion
Wejse [40] 2009 365 37 77 79 98 95 100,000 quarterly 12 months Sputum conversion
Martineau [41] 2011 146 31 21 21 101 23 4 × 100,000 6 days Sputum conversion
Salahuddin [42] 2013 259 28 52 58 220 50 2 × 600,000 12 weeks Sputum conversion
Ralph [43] 2013 200 28 ND ND ND ND 50,000 monthly 8 weeks Sputum conversion
Daley [44] 2015 247 43 58 54 72 60 100,000 quarterly 12 months Sputum conversion
Fig. 2 Meta-analysis of the efficacy of vitamin D therapy against tuberculosis. Results are presented as odds ratios. Error bars indicate 95 % confi-
dence intervals
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Zittermann et al. Eur J Med Res (2016) 21:14
e results on acute respiratory tract infection are par-
ticularly interesting for two reasons: firstly, the data prove
that vitamin D, in addition to its effects on the muscu-
loskeletal system, also possesses other important func-
tions of clinical relevance. Secondly, the data show that
attention must be paid to the vitamin D supply not only
during infancy and old age but also in otherwise healthy
children and adults. Notably, the winter nadir in vitamin
D status parallels the winter peak in airway infections.
As viral infections of the respiratory tract often pre-
cede bacterial infections, the results of a post hoc analy-
sis of the RECORD trial [70], a prospective randomised
study with 5300 participants who received either 800IU
of vitamin D or a placebo daily for two to 5years, are
interesting: in the vitamin D group, there was a ten-
dency towards fewer self-reported infections (of any
cause) and antibiotics use. Results are in line with data by
Bergman etal. on respiratory tract infection [59], dem-
onstrating a 63.5% reduction in the taking of antibiot-
ics in the vitamin D group. In another post hoc analysis
of a vitamin D study, an age-related effect of vitamin D
on antibiotic intake was observed [71]: while vitamin D
supplements did not reduce antibiotic intake in people
under 70years of age, patients aged 70years and older in
the control group required considerably more antibiotics
than those in the vitamin D group. Although the results
of the aforementioned three studies are provisional, and
further studies on reduction of the need for antibiotics
due to vitamin D are necessary, they provide promising
evidence of a role of protective vitamin D effects on res-
piratory tract infections. Altogether, likely evidence exists
that a sufficient vitamin D supply can prevent URTI.
Molecular eects ofvitamin D onthe immune
system
Molecular vitamin D effects on the immune system may
explain the protective clinical associations observed
(Table 3). Since the 1980s, it has become increasingly
clear that vitamin D plays a prominent role in innate
immunity. Vitamin D receptors are found on mono-
cytes. ese cells differentiate into macrophages under
the influence of 1,25(OH)2D [72]. Macrophages express
their own 1α-hydroxylase isoenzyme which intracellu-
larly synthesises the active 1,25(OH)2D. e activity of
Table 2 Randomised, controlled trials ofvitamin D forprevention ofrespiratory tract infections
25OHD 25-hydroxyvitamin D; IU international units; ND not determined; URTI upper respiratory tract infection; RTI respiratory tract infection
a signicantly higher than placebo
b signicantly lower than vitamin D group
c several studies were included. The vitamin D doses in the individual studies were as follows: 2000, 2800 and 6800IU/daily, 20,000 and 40,000IU/weekly and 100,000/
monthly, every 2months or every 3months
d initial dose: 200,000IU
Author (ref.) Publication
year N
(total) Age
(years) 25OHD
(nmol/l) 25OHD
(nmol/l) Mean vitamin D
dose (IU) Duration Endpoint
Initial In-study
Vit D Placebo Vit D Placebo
Aloia [54] 2007 208 60.6 46.9 43 86.9 43 800/2000 daily 3 years Influenza
Li-Ng [55] 2009 148 58.7 58.7 63 88.5 60.9 2000 daily 3 months URTI
Laaksi [52] 2010 164 Young men 78.7 74.4 72 51 400 daily 6 months Acute RTI
Manaseki-Holland
[56]2010 453 1.2 ND ND ND ND 100,000 (single dose) 3 weeks Pneumonia
Urashima [57] 2010 334 10.2 ND ND ND ND 1200 daily 4 months Influenza A
Majak [58] 2011 48 11.5 64.3 88 94 80 500 daily 6 months Acute RTI
Bergman [59] 2012 124 53.1 51.5 46.9 117.4 44 4000 daily 12 months RTI
Camargo [60] 2012 244 19.9 17.5 17 47.3 18 300 daily 7 weeks Acute RTI
Jorde [61] 2012 569 63 ND ND ND ND 3344c12 months Influenza-like
Manaseki-Holland
[62]2012 3046 0.8 ND ND a b 100,000 quarterly 18 months Pneumonia
Murdoch [63] 2012 322 47.5 75.5 70 122.5 55 100,000 monthlyd18 months URTI
Rees [64] 2013 759 58.1 62 63.1 ND ND 1000 daily 3–5 years URTI
Urashima [65] 2014 247 Students ND ND ND ND 2000 daily 2 months Influenza A
Goodall [66] 2014 471 19 ND ND ND ND 10,000 weekly 2 months URTI
Simpson [67] 2015 34 Healthy adults 60.5 76.4 107 46 20,000 weekly 17 weeks RTI
Martineau [68] 2015 250 47.9 49.8 49.4 69.4 46.5 120,000 bimonthly 1 year Acute RTI
Content courtesy of Springer Nature, terms of use apply. Rights reserved.
Page 7 of 10
Zittermann et al. Eur J Med Res (2016) 21:14
this enzyme is increased in activated macrophages [73].
During phagocytosis, macrophages incorporate patho-
gens such as MTB in the so-called phagosomes. Human
macrophages which are infected with MTB show higher
expression of the intracellular vitamin D receptor and of
the 1α-hydroxylase in human macrophages than native
macrophages [30]. 1,25(OH)2D directly and indirectly
regulates the expression of cathelicidin and defensins,
respectively [28, 30]. Cathelicidin induces the fusion
of inactive phagosomes with active autophagosomes
[74]. Under the further influence of cathelicidin, the
autophagosomes can fuse with lysosomes to the autol-
ysosome [75]. As the next weapon of innate immunity,
1,25(OH)2D induces the expression of lysosomal enzymes
and of reactive oxygen species like nitric oxide, ultimately
leading to increased antimicrobial activity [75]. e com-
bination of antimicrobial peptides and oxygen species
may destroy intracellular viruses, fungi, and bacteria in
the autolysosomes. Due to cathelicidin’s antiviral effects,
it supports host defence against influenza virus or human
immunodeficiency virus [76]. Notably, monocytic cathel-
icidin production is reduced in individuals with insuffi-
cient 25OHD or low 1,25(OH)2D levels [77].
e vitamin D innate host response is also active in
many other cells like keratinocytes, gastrointestinal/
bronchial epithelial cells, decidual cells, trophoblas-
tic cells and natural killer cells [76, 78]. Accordingly,
vitamin D bacterial action is broad-reaching and can
provide protection against various pathogens, especially
in airway infections [76]. By inducing the expression of
defensins, vitamin D seems indirectly to help blocking
of the membrane fusion mediated by viral hemaggluti-
nin, which might partly explain the antiviral potential
that is ascribed to vitamin D, particularly with regard to
influenza [57]. Finally, vitamin D plays a role in acquired
immunity directly by acting on T cells and indirectly
by regulating dendritic cells [76]. Vitamin D-mediated
induction of immunoglobulin E expression together with
eosinophil granulocytes supports the elimination of some
extracellular pathogens like parasites or fungi [79]. Vita-
min D also restricts 1/17 cell differentiation and
favours 2 differentiation [76]. High vitamin D levels
seem to be concomitant with decreased pro-inflamma-
tory cytokines, which might have a positive effect on
disease progression [57, 80]. Conversely, a low vitamin
D status is associated with an activation of inflammatory
processes [81]. Since it takes approximately 48h between
antigen recognition and full T cell activation, it has been
speculated that if the innate immune system is able to
clear the infection rapidly, the vitamin D-mediated delay
of full T cell activation puts the brakes on excessive T cell
proliferation to avoid immunopathology [76].
Conclusion
Vitamin D is an essential substance for the human body,
but large population-based studies demonstrate that
Fig. 3 Meta-analysis of the efficacy of vitamin D therapy against acute airway infections. Results are presented as odds ratios. Error bars indicate
95 % confidence intervals
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Page 8 of 10
Zittermann et al. Eur J Med Res (2016) 21:14
vitamin D deficiency is widespread in Europe. Institu-
tionalised individuals and non-European immigrants
are most affected. Moreover, the proportion of the lat-
ter group in European TB cases is high. erefore, non-
European immigrants would probably benefit from
improving their vitamin D status. Present data indicate
that vitamin D deficiency increases the risk of acute air-
way infection. Of note, there is also evidence that vita-
min D can lower the risk of other common infections like
sepsis, human immunodeficiency virus and hepatitis C
virus [76, 8286]. Due to the available evidence, the high
prevalence of deficient vitamin D status in the general
European population, and taking into consideration the
benefit/risk ratio, vitamin D supplementation can there-
fore be considered for infection prophylaxis. Oral vita-
min D needs are increased, particularly in winter, due
to the lower solar UVB radiation at this time of the year.
Recommended oral vitamin D intakes of different nutri-
tion, osteoporosis and endocrine societies vary between
600 and 2000IU daily [10, 11, 14, 87, 88]. However, so
far, recommendations have primarily been based on mus-
culoskeletal health and mortality. Regardless of whether
airway infection is considered, there is general agree-
ment that the lower target circulating 25OHD should be
50nmol/l. From a recently published systematic review
of RCTs, it can be concluded that, in the majority of peo-
ple, daily intake of 1000IU should result in circulating
25OHD levels>50nmol/l [89]. us, it is reasonable and
safe to take approximately 1000IU of vitamin D daily to
optimise non-specific immunity and prevent infection.
When doing so, it is important to start supplementation
in early autumn in order to ensure an adequate vitamin D
level in winter. Supplementation should also take place all
year round in people with an increased risk of vitamin D
deficiency like office workers, non-European immigrants
and frail elderly people. Vitamin D supplements are inex-
pensive (approx. 6,/100 tablets = 22,/year) and
have the advantage that they target not only the immune
system but also other tissues like the musculoskeletal
system.
Authors’ contributions
AZ, SP and WM designed the manuscript and acquired the data. AZ drafted
the manuscript. HH reviewed the manuscript for important intellectual con-
tent. All authors read and approved the final manuscript.
Author details
1 Department of Thoracic and Cardiovascular Surgery, NRW Heart and Dia-
betes Centre, Clinic for Thoracic and Cardiovascular Surgery, Ruhr University
of Bochum, Georgstraße 11, 32545 Bad Oeynhausen, Germany. 2 Department
of Endocrinology and Metabolism, Medical University of Graz, Graz, Austria.
3 Synlab MVZ Gauting, Institute of Microbiology and Laboratory Medicine,
WHO Supranational Reference Laboratory of Tuberculosis, Gauting, Germany.
4 Synlab Academy for Continuing Medical Education, Mannheim und Synlab
Services GmbH, Augsburg, Germany. 5 Clinical Institute for Medical and Chem-
ical Laboratory Diagnostics, Medical University of Graz, Graz, Austria. 6 Depart-
ment of Medicine V (Nephrology, Hypertension, Rheumatology, Endocrinol-
ogy, Diabetology) Mannheim Faculty of Medicine, University of Heidelberg,
Heidelberg, Germany.
Acknowledgements
None.
Competing interests
The authors declare that they have no competing interests.
Received: 11 November 2015 Accepted: 16 March 2016
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... Vitamin D (VitD) deficiency and insufficiency are global health issues, posing a major public health risk [1,2]. Poor VitD status is connected with skeletal and non-skeletal health issues, including the functioning of the immune system [3][4][5][6][7]. Maintenance of an optimal VitD status is therefore of the utmost importance. ...
... Very low dietary intake of VitD in the Slovenian population, shown in our study, partially explains the previously reported high prevalence of VitD deficiency during winter, when sun-induced biosynthesis of VitD is not sufficient [11]. While the public health outcomes of this epidemiological situation have not been well investigated, it should be mentioned that VitD is a key component in various bodily functions [3][4][5][6][7], also related to the functioning of the immune system and bone health. Although this study did not address this topic, it should be mentioned that Slovenia has been among the countries with the most severe death toll from COVID-19 (currently 2,174 deaths/1 mio. ...
Article
Full-text available
Vitamin D is involved in calcium and phosphorus metabolism, and is vital for numerous bodily functions. In the absence of sufficient UV-B light-induced skin biosynthesis, dietary intake becomes the most important source of vitamin D. In the absence of biosynthesis, the recommended dietary vitamin D intake is 10–20 µg/day. Major contributors to dietary vitamin D intake are the few foods naturally containing vitamin D (i.e., fish), enriched foods, and supplements. The present study aimed to estimate the vitamin D intake in Slovenia, to identify food groups that notably contribute to vitamin D intake, and to predict the effects of hypothetical mandatory milk fortification. This study was conducted using data collected by the national cross-sectional food consumption survey (SI.Menu) in adolescents (n = 468; 10–17 years), adults (n = 364; 18–64 years), and the elderly (n = 416; 65–74 years). Data collection was carried out between March 2017 and April 2018 using the EU Menu Methodology, which included two 24-hour recalls, and a food propensity questionnaire. Very low vitamin D intakes were found; many did not even meet the threshold for very low vitamin D intake (2.5 µg/day). Mean daily vitamin D intake was 2.7, 2.9, and 2.5 µg in adolescents, adults, and the elderly, respectively. Daily energy intake was found to be a significant predictor of vitamin D intake in all population groups. In adolescents and adults, sex was also found to be a significant predictor, with higher vitamin D intake in males. The study results explained the previously reported high prevalence of vitamin D deficiency in Slovenia. An efficient policy approach is required to address the risk of vitamin D deficiency, particularly in vulnerable populations.
... Vitamin D is critical for bone and mineral metabolism and is effective in the prevention and treatment of rickets and osteomalacia (1,2,3,4,5). Given that vitamin D receptors (VDRs) are expressed in almost every tissue and cell, there have been numerous investigations on potential extra-skeletal effects of vitamin D (6,7,8,9,10,11,12,13,14). Epidemiological studies showed that low 25-hydroxyvitamin D (25[OH]D) concentrations are associated with various acute and chronic diseases, thus raising a high interest in vitamin D (15,16). ...
... Beyond musculoskeletal effects, several studies investigated the potential extra-skeletal actions of vitamin D. Cell culture and animal studies as well as observational data support the hypothesis that vitamin D is critical for a variety of common diseases including for example, cardiovascular, autoimmune, and neurological diseases, infections, pregnancy complications and cancer (1,6,7,8,9,10,11,12,13,14,15,16,17,18,19,20). By contrast, RCTs have largely shown no effect of vitamin D supplementation on nonskeletal health outcomes (7,17,18,19,20,58,59,60,61,62,63,64,65,66). ...
... Meta-analyses of vitamin D RCTs suggest that vitamin D supplementation may reduce the incidence of acute respiratory infections, cancer mortality, as well as asthma and chronic obstructive pulmonary disease (COPD) exacerbations [5,96,[102][103][104][105][106][107][108]. Considering the totality of evidence regarding vitamin D and a variety of extra-skeletal diseases, we are of the opinion that it is justified to consider screening and preventive vitamin D supplementation in certain populations at risk (see Table 8). ...
Article
Full-text available
Vitamin D deficiency has a high worldwide prevalence, but actions to improve this public health problem are challenged by the heterogeneity of nutritional and clinical vitamin D guidelines, with respect to the diagnosis and treatment of vitamin D deficiency. We aimed to address this issue by providing respective recommendations for adults, developed by a European expert panel, using the Delphi method to reach consensus. Increasing the awareness of vitamin D deficiency and efforts to harmonize vitamin D guidelines should be pursued. We argue against a general screening for vitamin D deficiency but suggest 25-hydroxyvitamin D (25(OH)D) testing in certain risk groups. We recommend a vitamin D supplementation dose of 800 to 2000 international units (IU) per day for adults who want to ensure a sufficient vitamin D status. These doses are also recommended for the treatment of vitamin D deficiency, but higher vitamin D doses (e.g., 6000 IU per day) may be used for the first 4 to 12 weeks of treatment if a rapid correction of vitamin D deficiency is clinically indicated before continuing, with a maintenance dose of 800 to 2000 IU per day. Treatment success may be evaluated after at least 6 to 12 weeks in certain risk groups (e.g., patients with malabsorption syndromes) by measurement of serum 25(OH)D, with the aim to target concentrations of 30 to 50 ng/mL (75 to 125 nmol/L).
... Vitamin D (VitD) is a fat-soluble vitamin family usually encompassing ergocalciferol (D2) and cholecalciferol (D3) (1,2). It is a pro-hormone with a well-established role in musculoskeletal health and other functions (3)(4)(5). Discussion about the importance of sufficient VitD status during the COVID-19 epidemic should also be mentioned (6)(7)(8)(9), but consensus has not yet been reached on this topic. ...
Article
Full-text available
Vitamin D deficiency is a worldwide public health concern, which can be addressed with voluntary or mandatory food fortification. The aim of this study was to determine if branded food composition databases can be used to investigate voluntary fortification practices. A case study was conducted using two nationally representative cross-sectional datasets of branded foods in Slovenia, collected in 2017 and 2020, and yearly sales data. Using food labeling data we investigated prevalence of fortification and average vitamin D content, while nutrient profiling was used to investigate overall nutritional quality of the foods. In both datasets, the highest prevalence of vitamin D fortification was observed in meal replacements (78% in 2017; 100% in 2020) and in margarine, corresponding to high market share. Other food categories commonly fortified with vitamin D are breakfast cereals (5% in 2017; 6% in 2020), yogurts and their imitates (5% in 2017; 4% in 2020), and baby foods (18% in both years). The highest declared average content of vitamin D was observed in margarine and foods for specific dietary use (7–8 μg/100g), followed by breakfast cereals (4 μg/100g), while the average content in other foods was below 2 μg/100g. Only minor differences were observed between 2017 and 2020. Major food-category differences were also observed in comparison of the overall nutritional quality of the fortified foods; higher overall nutritional quality was only observed in fortified margarine. Our study showed that branded food composition databases are extremely useful resources for the investigation and monitoring of fortification practices, particularly if sales data can also be used. In the absence of mandatory or recommended fortification in Slovenia, very few manufacturers decide to add vitamin D, and even when this is the case, such products are commonly niche foods with lower market shares. We observed exceptions in imported foods, which can be subject to fortification policies introduced in other countries.
... However, genetic variation in the Vitamin D receptor gene was suggested to modify the effects of adjunctive Vitamin D3 in TB patients (Jolliffe et al., 2016). Additionally, multiple randomized trials suggested that adjunctive Vitamin D treatment has limited effect in improving clinical and immunologic outcomes during active Mtb infection despite evidence that specific VDR polymorphisms are predictive of sputum conversion time (Xia et al., 2014;Grobler et al., 2016;Zittermann et al., 2016). A phase 2 clinical study in TB patients (NCT02968927) assess the anti-inflammatory effects of Vitamin D3 in combination with 3 other adjunctive HDT compounds: CC-11050, Everolimus and Auranofin (Wallis et al., 2021). ...
Article
Full-text available
Immunity against Mycobacterium tuberculosis (Mtb) is highly complex, and the outcome of the infection depends on the role of several immune mediators with particular temporal dynamics on the host microenvironment. Autophagy is a central homeostatic mechanism that plays a role on immunity against intracellular pathogens, including Mtb. Enhanced autophagy in macrophages mediates elimination of intracellular Mtb through lytic and antimicrobial properties only found in autolysosomes. Additionally, it has been demonstrated that standard anti-tuberculosis chemotherapy depends on host autophagy to coordinate successful antimicrobial responses to mycobacteria. Notably, autophagy constitutes an anti-inflammatory mechanism that protects against endomembrane damage triggered by several endogenous components or infectious agents and precludes excessive inflammation. It has also been reported that autophagy can be modulated by cytokines and other immunological signals. Most of the studies on autophagy as a defense mechanism against Mycobacterium have been performed using murine models or human cell lines. However, very limited information exists about the autophagic response in cells from tuberculosis patients. Herein, we review studies that face the autophagy process in tuberculosis patients as a component of the immune response of the human host against an intracellular microorganism such as Mtb. Interestingly, these findings might contribute to recognize new targets for the development of novel therapeutic tools to combat Mtb. Actually, either as a potential successful vaccine or a complementary immunotherapy, efforts are needed to further elucidate the role of autophagy during the immune response of the human host, which will allow to achieve protective and therapeutic benefits in human tuberculosis.
... The most important dietary sources of VitD were eggs, fish, and fish products, and meat and meat products (19). (74) is related to a growing body of evidence that connects sufficient 25(OH)D status with better health outcomes (75)(76)(77)(78), while highlighting the high prevalence of VitD deficiency in different populations (13). This topic has recently gained even more attention due to the possible associations of VitD status with health outcomes of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infected patients (78)(79)(80)(81)(82). ...
Article
Full-text available
Aim Vitamin D (VitD) is involved in calcium and phosphate homeostasis, bone health, and normal functioning of the immune system. VitD status is monitored using serum 25-hydroxy-vitamin D (25(OH)D) as a biomarker. Serum 25(OH)D concentrations below 30 nmol/L indicate VitD deficiency and below 50 nmol/L indicate insufficiency. VitD can be synthesised endogenously in human skin when exposed to ultraviolet B (UVB) radiation. In the absence of sufficient UVB-light exposure, VitD intake becomes the main source of VitD, with a recommended daily intake of 20 μg. The aim of this study was to conduct a review and meta-analysis on the abovementioned topics, focusing on scientific studies in various Slovenian populations. Methods We conducted a systematic review and meta-analysis of published scientific papers, academic theses, or conference contributions reporting serum 25(OH)D status and VitD intake across various Slovenian populations. A search was carried out using Web of Science, Scopus, Medline, and the Slovenian library database. Results We identified 43 pertinent studies that addressed 25(OH)D status and 16 that addressed VitD intake. Serum 25(OH)D status was generally low across all populations, and notable seasonal variability was observed. VitD intakes were below 5 μg in all studies. Conclusions A general observation is that various population groups across Slovenia are at high risk of vitamin D insufficiency and deficiency, particularly during wintertime. Regarding vitamin D intake, all included studies reported daily intakes below the recommended level. We also identified key research gaps that need to be addressed to support further public health decision-making.
... Vitamin D is a key regulator of calcium and phosphorous metabolism in children and adults [6] and is critical for bone health [7], through the mediation of osteogenic-related mineral absorption and utilization for skeletal development and maintenance [1]. Furthermore, due to the presence of vitamin D receptors expressed in almost every tissue and cell, there have been a substantial number of investigations into the effects of vitamin D that are extra-skeletal [8][9][10][11][12][13][14][15]. Moreover, there are current investigations into the impact of vitamin D on COVID-19 [16], with recent systemic reviews and meta-analyses revealing that low serum 25(OH)D is significantly associated with a higher risk of COVID-19 infection and severity [17,18]. ...
Article
Full-text available
Vitamin D deficiency is a serious public health issue in the United Kingdom. Those at increased risk, such as pregnant women, children under 5 years and people from ethnic groups with dark skin, are not all achieving their recommended vitamin D. Effective vitamin D education is warranted. A qualitative study was undertaken to evaluate the acceptability and understanding of a vitamin D infographic, developed using recommendations from previous research. Fifteen parents/carers, recruited through local playgroups and adverts on popular parent websites, participated in focus groups and telephone interviews. The majority were female, White British and educated to degree level. A thematic analysis methodology was applied. The findings indicated that understanding and acceptability of the infographic were satisfactory, but improvements were recommended to aid interpretation and create more accessible information. These included additional content (what vitamin D is; other sources; its health benefits; methods/doses for administration and scientific symbols used) and improved presentation (eye-catching, less text, simpler language, more images and a logo). Once finalized, the infographic could be a useful tool to educate families around vitamin D supplementation guidelines, support the UK Healthy Start vitamins scheme and help improve vitamin D status for pregnant and lactating women and young children.
Article
Full-text available
Slowed information processing speed (IPS) is the hallmark and first cognitive domain to be altered in multiple sclerosis (MS) patients. Insufficient serum vitamin D was previously associated with disease development, relapses, and progression, but little is reported on cognition. However, vitamin D and cognitive impairment (CI) in other neurodegenerative diseases have already been linked. We explored the possible correlation between vitamin D and IPS at diagnosis and early disability at last follow-up in 81 MS patients. At diagnosis, we collected vitamin D levels and performed a Symbol Digit Modalities Test (SDMT). Raw scores were adjusted for age, gender, and educational level. Early disability was evaluated with MS severity score (MSSS) and age-related MSSS (ARMSS). A total of 71 patients (86.58%) showed hypovitaminosis D (19.71 ± 8.76 ng/mL) and 18 patients (21.95%) had CI. Patients with CI showed severe hypovitaminosis D (p = 0.004). No patients with sufficient vitamin D levels had CI. We found a positive correlation between vitamin D levels at diagnosis and (1) SDMT raw and z-score that persisted after correction for sunlight exposure and MRI baseline characteristics, and (2) EDSS, MSSS, and ARMSS after a mean 2 year follow-up. Low vitamin D levels may affect both cognition and early disability in newly diagnosed MS patients.
Article
Primary ciliary dyskinesia (PCD) is a genetic disease characterized by abnormalities in ciliary structure/function. The diagnosis of PCD relies on a combination of clinical evaluation and ultrastructural (electron microscopic) analysis of the ciliary architecture. This diagnosis may be challenging due to clinical and genetic heterogeneity and artifacts during the ciliary ultrastructure preparation and assessment. Recently, vitamin D supplementation has been proposed for several groups probably suffering from D-hypovitaminosis. Some patients with inflammatory bowel disease may have significant malabsorption, and vitamin D supplementation in these patients is recom-mended. Two recent reports suggest that a low plasmatic level of this vitamin is present in the PCD population. The utility of vitamin D supplementation may be essential in this group of individ-uals, and further investigations are warranted. Still, in examining the literature papers, it seems relevant that the authors concentrate solely on lung function in both studies. Future studies should probably target the intestinal function in patients with PCD independently from the vitamin D supplementation to fully evaluate its role.
Article
Full-text available
Background: Vitamin D deficiency has been described as being pandemic, but serum 25-hydroxyvitamin D [25(OH)D] distribution data for the European Union are of very variable quality. The NIH-led international Vitamin D Standardization Program (VDSP) has developed protocols for standardizing existing 25(OH)D values from national health/nutrition surveys. Objective: This study applied VDSP protocols to serum 25(OH)D data from representative childhood/teenage and adult/older adult European populations, representing a sizable geographical footprint, to better quantify the prevalence of vitamin D deficiency in Europe. Design: The VDSP protocols were applied in 14 population studies [reanalysis of subsets of serum 25(OH)D in 11 studies and complete analysis of all samples from 3 studies that had not previously measured it] by using certified liquid chromatography-tandem mass spectrometry on biobanked sera. These data were combined with standardized serum 25(OH)D data from 4 previously standardized studies (for a total n = 55,844). Prevalence estimates of vitamin D deficiency [using various serum 25(OH)D thresholds] were generated on the basis of standardized 25(OH)D data. Results: An overall pooled estimate, irrespective of age group, ethnic mix, and latitude of study populations, showed that 13.0% of the 55,844 European individuals had serum 25(OH)D concentrations <30 nmol/L on average in the year, with 17.7% and 8.3% in those sampled during the extended winter (October-March) and summer (April-November) periods, respectively. According to an alternate suggested definition of vitamin D deficiency (<50 nmol/L), the prevalence was 40.4%. Dark-skinned ethnic subgroups had much higher (3- to 71-fold) prevalence of serum 25(OH)D <30 nmol/L than did white populations. Conclusions: Vitamin D deficiency is evident throughout the European population at prevalence rates that are concerning and that require action from a public health perspective. What direction these strategies take will depend on European policy but should aim to ensure vitamin D intakes that are protective against vitamin D deficiency in the majority of the European population.
Article
Full-text available
Background/aim: Mixed Cryoglobulinemia (MC) represents the most frequent extrahepatic manifestation of chronic Hepatitis C Virus (HCV) infection. Its pathogenic mechanisms involve HCV-induced chronic stimulation of B-lymphocytes. We aimed to investigate the relationship between serum levels of vitamin D (a regulator of immune response) and the presence of serum cryoglobulins in the setting of HCV infection. Patients and methods: We evaluated the serum concentration of 25(OH)vitamin D and cryoglobulins in 106 patients with chronic HCV infection. Results: Thirty patients (28.3%) showed the presence of serum cryoglobulins. For the cohort overall, the median serum 25(OH)vitamin D level was 10.95 ng/ml. Patients with serum cryoglobulins had significantly lower levels of 25(OH)vitamin D (5.61 ng/ml) than those without (13.65 ng/ml, p=0.029). At multivariate analysis, severe hypovitaminosis [i.e. 25(OH)vitamin D <13 ng/ml] was the only independent predictor of cryoglobulinemia (odds ratio=3.108). Conclusion: Severe deficiency of vitamin D was independently associated with mixed cryoglobulinemia in patients with HCV infection.
Article
Full-text available
Within the last decade, vitamin D has emerged as a central regulator of host defense against infections. In this regard, vitamin D triggers effective antimicrobial pathways against bacterial, fungal and viral pathogens in cells of the human innate immune system. However, vitamin D also mediates potent tolerogenic effects: it is generally believed that vitamin D attenuates inflammation and acquired immunity, and thus potentially limits collateral tissue damage. Nevertheless, several studies indicate that vitamin D promotes aspects of acquired host defense. Clinically, vitamin D deficiency has been associated with an increased risk for various infectious diseases in epidemiological studies; yet, robust data from controlled trials investigating the use of vitamin D as a preventive or therapeutic agent are missing. In this review, we summarize the current knowledge regarding the effect of vitamin D on innate and acquired host defense, and speculate on the difficulties to translate the available molecular medicine data into practical therapeutic or preventive recommendations.
Article
Full-text available
Hypovitaminosis D is a worldwide disorder, with a high prevalence in the general population of both Western and developing countries. In HIV patients, several studies have linked vitamin D status with bone disease, neurocognitive impairment, depression, cardiovascular disease, high blood pressure, metabolic syndrome, type 2 diabetes mellitus, infections, autoimmune diseases like type 1 diabetes mellitus, and cancer. In this review, we focus on the most recent epidemiological and experimental data dealing with the relationship between vitamin D deficiency and HIV infection. We analysed the extent of the problem, pathogenic mechanisms, clinical implications, and potential benefits of vitamin D supplementation in HIV-infected subjects.
Article
Background: Observational studies have linked vitamin D status and infectious disease. This association is supported by the presence of the vitamin D receptor and CYP27B1 in immune cells. This review aims to consolidate data from clinical trials that used vitamin D for the treatment or prevention of infectious disease. Methods: The authors searched the term "(vitamin D OR ergocalciferol OR cholecalciferol OR vitamin D2 OR vitamin D3 OR calcitriol) AND (infection OR tuberculosis OR sepsis OR pneumonia)" with limits preset to manuscripts published in English and with human subjects. They identified controlled trials that measured infectious outcomes (eg, incidence and severity of disease, time to disease resolution or recurrence, measures of clinical improvement, mortality). Studies that used analog, topical or micronutrient formulations of vitamin D, assessed only vitamin D status or lacked a comparison group were excluded. The references from eligible manuscripts and from 2 recent reviews were scanned for additional manuscripts. Results: One thousand two hundred eighty-four manuscripts were identified with our search terms, with 60 papers still eligible after review of the title and abstract. Full review of these papers, their references and 2 related reviews yielded 38 manuscripts. Conclusions: Although some prospective studies show positive results regarding vitamin D on infectious disease, several robust studies are negative. Factors such as high variability between studies, the difference in individual responsiveness to vitamin D and study designs that do not primarily investigate infectious outcomes may mask the effects of vitamin D on infections.
Article
Observational studies suggest vitamin D deficiency may contribute to the risk of acute infections. We undertook a randomised controlled trial (RCT) of cholecalciferol supplementation as an intervention against acute infections. A cohort of 34 healthy adults was randomised to 20,000 IU/week cholecalciferol or identical placebo and followed for 17 weeks during winter 2012. Acute infections, defined as the occurrence of sustained (at least an hour) infection symptoms, either of severity 2/5 or greater or sustained over 24 h, were monitored by daily online symptom reporting, with potential infections assessed in clinic. No microbiological verification of symptoms was available, however. Primary endpoint was the occurrence of acute infection; secondary endpoints were infection duration and infection severity; and tertiary endpoints were change in serum 25-hydroxyvitamin D (25(OH)D) and adverse events. No treatment effect was observed for infection risk (HR: 0.83, 95% CI: 0.53, 1.31), nor duration or severity. However, on stratification by baseline serum 25(OH)D (levels chosen on the basis of average levels in our cohort and known minimums needed for bone health), a significant treatment effect on infection risk was evident among those who were vitamin D deficient at the start of the study, such that those of baseline 25(OH)D < 40 nmol/L (n = 4) realised a 44% reduction in infection risk (HR: 0.56; 95% CI: 0.32, 0.96; P = 0.007), this increasing to 73% on restriction to clinically verified infections (HR: 0.27; 95% CI: 0.07, 1.00; P = 0.050). A similar but less consistent and nonsignificant effect was seen for infection severity. Treatment was associated with significantly higher 25(OH)D compared to placebo; however, the maximum 25(OH)D was 154 nmol/L and no adverse events occurred. The results of this study suggest a protective effect of vitamin D supplementation against acute infection risk among persons who are vitamin D deficient. Larger studies are needed to validate these findings.
Article
Rationale Low-dose vitamin D supplementation is already recommended in older adults for prevention of fractures and falls, but clinical trials investigating whether higher doses could provide additional protection against acute respiratory infection (ARI) are lacking. Objective To conduct a clinical trial of high-dose versus low-dose vitamin D3 supplementation for ARI prevention in residents of sheltered-accommodation housing blocks (‘schemes’) and their carers in London, UK. Measurements and methods Fifty-four schemes (137 individual participants) were allocated to the active intervention (vitamin D3 2.4 mg once every 2 months +10 μg daily for residents, 3 mg once every 2 months for carers), and 54 schemes with 103 participants were allocated to control (placebo once every 2 months +vitamin D3 10 μg daily for residents, placebo once every 2 months for carers) for 1 year. Primary outcome was time to first ARI; secondary outcomes included time to first upper/lower respiratory infection (URI/LRI, analysed separately), and symptom duration. Main results Inadequate vitamin D status was common at baseline: 220/240 (92%) participants had serum 25(OH)D concentration <75 nmol/L. The active intervention did not influence time to first ARI (adjusted HR (aHR) 1.18, 95% CI 0.80 to 1.74, p=0.42). When URI and LRI were analysed separately, allocation to the active intervention was associated with increased risk of URI (aHR 1.48, 95% CI 1.02 to 2.16, p=0.039) and increased duration of URI symptoms (median 7.0 vs 5.0 days for active vs control, adjusted ratio of geometric means 1.34, 95% CI 1.09 to 1.65, p=0.005), but not with altered risk or duration of LRI. Conclusions Addition of intermittent bolus-dose vitamin D3 supplementation to a daily low-dose regimen did not influence risk of ARI in older adults and their carers, but was associated with increased risk and duration of URI. Trial registration number clinicaltrials.gov NCT01069874.