Vitamin d ref

Vitamin D References

Eur J Clin Nutr. 2004 Apr;58(4):563-7.

Association of subclinical vitamin D deficiency with severe acute lower
respiratory infection in Indian children under 5 y.
Wayse V, Yousafzai A, Mogale K, Filteau S.

Source
Centre for International Child Health, Institute of Child Health, University College
London, London, UK.
Abstract
OBJECTIVES:
To determine whether subclinical vitamin D deficiency in Indian children under 5 y of age
is a risk factor for severe acute lower respiratory infection (ALRI).
DESIGN:
A hospital-based case-control study.
SETTING:
Sanjeevani Paediatrics Hospital, a private hospital in Indapur, India.
PARTICIPANTS:
A total of 150 children including 80 cases and 70 controls, aged 2-60 months, were
enrolled. Case definition of severe ALRI as given by the World Health Organization was
used for cases. Controls were healthy children attending outpatients' service for
immunization.
MAIN OUTCOME MEASURE:
Association of serum 25-hydroxyvitamin D3 (25OHD3) with severe ALRI, controlling for
demographic and other potential risk factors.
RESULTS:
Serum 25OHD3 increased with age. Factors significantly associated with decreased risk
of severe ALRI in univariate analysis were: exclusive breastfeeding in the first 4 months
(cases 35/78 (45%), controls 41/64 (64%); P=0.02); introduction of other dietary
liquids than milk only after 6 months (cases 46/70 (66%), controls 31/66 (47%);
P=0.03); use of liquid petroleum cooking fuel (cases 32/80 (40%), controls 40/70
(57%); P=0.04); infant not covered in swaddling cloths when exposed to sunlight before
crawling (cases 11/52 (21%), controls 25/54 (46%); P=0.006); and serum
25OHD3>22.5 nmol/l (cases 16/80 (20%), controls 48/70 (69%); P<0.001). In
multivariate analysis, factors associated with significantly lower odds ratio for having
severe ALRI were: serum 25OHD3>22.5 nmol/l (OR: 0.09; 95% CI 0.03-0.24; P<0.001)
and exclusive breastfeeding in the first 4 months of life (OR 0.42; 95% CI 0.18-0.99;
P=0.046) with age and height/age as significant covariates.
CONCLUSION:
Subclinical vitamin D deficiency and nonexclusive breastfeeding in the first 4 months of
life were significant risk factors for severe ALRI in Indian children.

Pediatrics. 2012 Aug 6. [Epub ahead of print]
Vitamin D Deficiency in Critically Ill Children.
Madden K, Feldman HA, Smith EM, Gordon CM, Keisling SM, Sullivan RM, Hollis
BW, Agan AA, Randolph AG.

Source
aDivision of Critical Care Medicine, Department of Anesthesia, Perioperative and Pain
Medicine.
Abstract
OBJECTIVE:
Vitamin D influences cardiovascular and immune function. We aimed to establish the
prevalence of vitamin D deficiency in critically ill children and identify factors influencing
admission 25-hydroxy vitamin D (25(OH)D) levels. We hypothesized that levels would
be lower with increased illness severity and in children with serious infections.
METHODS:
Participants were 511 severely or critically ill children admitted to the PICU from
November 2009 to November 2010. Blood was collected near PICU admission and
analyzed for 25(OH)D concentration by using Diasorin radioimmunoassay.
RESULTS:
We enrolled 511 of 818 (62.5%) eligible children. The median 25(OH)D level was 22.5
ng/mL; 40.1% were 25(OH)D deficient (level <20 ng/mL). In multivariate analysis, age
and race were associated with 25(OH)D deficiency; summer season, vitamin
D supplementation, and formula intake were protective; 25(OH)D levels were not lower
in the 238 children (46.6%) admitted with a life-threatening infection, unless they had
septic shock (n = 51, 10.0%) (median 25(OH)D level 19.2 ng/mL; P = .0008). After
adjusting for factors associated with deficiency, lower levels were associated with higher
admission day illness severity (odds ratio 1.19 for a 1-quartile increase in Pediatric Risk
of Mortality III score per 5 ng/mL decrease in 25(OH)D, 95% confidence interval 1.10-
1.28; P < .0001).
CONCLUSIONS:
We found a high rate of vitamin D deficiency in critically ill children. Given the roles
of vitamin D in bone development and immunity, we recommend screening of those
critically ill children with risk factors for vitamin D deficiency and implementation of
effective repletion strat

Eur J Clin Nutr. 2012 Jul 18. doi: 10.1038/ejcn.2012.82. [Epub ahead of print]
Impact of vitamin D supplementation on markers of inflammation in adults
with cystic fibrosis hospitalized for a pulmonary exacerbation.
Grossmann RE, Zughaier SM, Liu S, Lyles RH, Tangpricha V.

Source
Nutrition Health Sciences Program, Emory Graduate Division of Biological and Biomedical
Sciences, Emory University, Atlanta, GA, USA.
Abstract
Patients with cystic fibrosis (CF) suffer from chronic lung infection and inflammation
leading to respiratory failure. Vitamin D deficiency is common in patients with CF, and
correction of vitamin D deficiency may improve innate immunity and reduce
inflammation in patients with CF. We conducted a double-blinded, placebo-controlled,
randomized clinical trial of high-dose vitamin D to assess the impact of vitamin
D therapy on antimicrobial peptide concentrations and markers of inflammation. We
randomized 30 adults with CF hospitalized with a pulmonary exacerbation to 250 000 IU
of cholecalciferol or placebo, and evaluated changes in plasma concentrations of
inflammatory markers and the antimicrobial peptide LL-37 at baseline and 12 weeks
post intervention. In the vitamin D group, there was a 50.4% reduction in tumor
necrosis factor-α (TNF-α) at 12 weeks (P<0.01), and there was a trend for a 64.5%
reduction in interleukin-6 (IL-6) (P=0.09). There were no significant changes in IL-1β,
IL-8, IL-10, IL-18BP and NGAL (neutrophil gelatinase-associated lipocalin). We conclude
that a large bolus dose of vitamin D is associated with reductions in two inflammatory
cytokines, IL-6 and TNF-α. This study supports the concept that vitamin D may help
regulate inflammation in CF, and that further research is needed to elucidate the
potential mechanisms involved and the impact on clinical outcomes.European Journal of
Clinical Nutrition advance online publication,

Cytokine. 2012 Jul 14. [Epub ahead of print]
Effect of vitamin D(3) on chemokine expression in pulmonary tuberculosis.
Selvaraj P, Harishankar M, Singh B, Banurekha VV, Jawahar MS.

Source
Department of Immunology, National Institute for Research in Tuberculosis, Formerly
Tuberculosis Research Centre, Indian Council of Medical Research, 1, Sathyamoorthy
Road, Chennai 600 031, India.
Abstract
1,25 Dihydroxy vitamin D(3) (vitamin D(3)) is an immunomodulator and its deficiency
has been associated with susceptibility to tuberculosis. We have studied the
immunoregulatory role of vitamin D(3) on various chemokine expression in pulmonary
tuberculosis. Peripheral blood mononuclear cells obtained from 21 pulmonary
tuberculosis (PTB) patients and 24 healthy controls (HCs) were cultured for 48h with
culture filtrate antigen (CFA) of Mycobacterium tuberculosis with or without vitamin D(3)
at a concentration 1×10(-7)M. The relative mRNA expression of monocyte
chemoattractant protein-1 (MCP-1, CCL2), macrophage inflammatory protein-1α (MIP-
1α, CCL3), macrophage inflammatory protein-1β (MIP-1β, CCL4), and regulated upon-
activation, normal T cell-expressed and secreted (RANTES, CCL5) and IFN-γ inducible
protein-10 (IP-10, CXCL10) chemokines were estimated from 48h old macrophages
using real-time polymerase chain reaction (RT-PCR). The culture supernatants were
used to estimate the various chemokines including monokine induced by IFN-γ (MIG,
CXCL9) levels using cytometric bead array. In HCs, vitamin D(3) significantly suppressed
the MCP-1 mRNA expression of CFA stimulated cells (p=0.0027), while no such effect
was observed in PTB patients. Vitamin D(3) showed no significant effect on MIP-1α, MIP-
1β and RANTES in both the study groups. The CFA induced IP-10 mRNA and protein
expression was significantly suppressed by vitamin D(3) in both the study groups
(p<0.05). A similar suppressive effect of vitamin D(3) was observed with MIG protein in
healthy controls (p=0.0029) and a trend towards a suppression was observed in PTB
patients. The suppressive effect of vitamin D(3) is more prominent in CXC chemokines
rather than CC chemokines. This suggests that vitamin D(3) may down regulate the
recruitment and activation of T-cells through CXC chemokines at the site of infection and
may act as a potential anti-inflammatory agent.

J Proteomics. 2012 Jul 6. [Epub ahead of print]
Vitamin D binding protein isoforms as candidate predictors of disease
extension in childhood arthritis.
Gibson DS, Newell K, Evans AN, Finnegan S, Manning G, Scaife C, McAllister
C, Pennington SR, Duncan MW, Moore TL, Rooney ME.

Source
Arthritis Research Group, Queen's University of Belfast, Centre for Infection and
Immunity, Health Sciences Building 97 Lisburn Road, Belfast, BT9 7BL, UK; Division of
Endocrinology, Metabolism and Diabetes, School of Medicine, University of Colorado
Denver, 12800 E. 19th Ave., Aurora, CO 80045, USA.
Abstract
INTRODUCTION.: Juvenile idiopathic arthritis (JIA) comprises a poorly understood group
of chronic autoimmune diseases with variable clinical outcomes. We investigated
whether the synovial fluid (SF) proteome could distinguish a subset of patients in whom
disease extends to affect a large number of joints. METHODS.: SF samples from 57
patients were obtained around time of initial diagnosis of JIA, labeled with Cy dyes and
separated by two-dimensional electrophoresis. Multivariate analyses were used to isolate
a panel of proteins which distinguish patient subgroups. Proteins were identified using
MALDI-TOF mass spectrometry with expression verified by immunochemical methods.
Protein glycosylation status was confirmed by hydrophilic interaction liquid
chromatography. RESULTS.: A truncated isoform of vitamin D binding protein (VDBP) is
present at significantly reduced levels in the SF of oligoarticular patients at risk of
disease extension, relative to other subgroups (p<0.05). Furthermore, sialylated forms
of immunopurified synovial VDBP were significantly reduced in extended oligoarticular
patients (p<0.005). CONCLUSION.: Reduced conversion of VDBP to a macrophage
activation factor may be used to stratify patients to determine risk of disease extension
in JIA patients.

Br J Nutr. 2012 Apr 3:1-4. [Epub ahead of print]
Prevalence and severity of vitamin D deficiency in patients with diabetic
foot infection.
Tiwari S, Pratyush DD, Gupta B, Dwivedi A, Chaudhary S, Rayicherla RK, Gupta
SK, Singh SK.

Source
Department of Endocrinology and Metabolism, Institute of Medical Sciences, Banaras
Hindu University, Varanasi 221005, UP, India.
Abstract
The aim of the present research was to study the prevalence and severity of vitamin
D deficiency in patients with diabetic foot infection. Patients were enrolled in two groups:
diabetic patients with foot infection (n 125) as cases and diabetic patients without
the infection as controls (n 164). Serum 25-hydroxyvitamin D (25(OH)D) was measured
by RIA. Data were presented as means and standard deviations unless otherwise
indicated and were analysed by SPSS. Results revealed that 25(OH)D (nmol/l) was
significantly lower (40·25 (sd 38·35) v. 50·75 (sd 33·00); P < 0·001) in cases than in
controls. Vitamin D inadequacy (25(OH)D < 75 nmol/l) was equally common in cases
and controls (OR 1·45, 95 % CI 0·8, 3·0; P = 0·32), but cases had a greater risk
of vitamin D deficiency (25(OH)D < 50 nmol/l) than controls (OR 1·8, 95 % CI 1·1, 3·0;
P = 0·02). Risk of severe vitamin Ddeficiency (25(OH)D < 25 nmol/l) was significantly
higher in cases than in controls (OR 4·0, 95 % CI 2·4, 6·9; P < 0·0001). Age, duration
of diabetes and HbA1c were significantly higher in cases than in controls and therefore
adjusted to nullify the effect of these variables, if any, on study outcome. The study
concluded that vitamin D deficiency was more prevalent and severe in patients with
diabetic foot infection. This study opens up the issue of recognising severe vitamin
D deficiency ( < 25 nmol/l) as a possible risk factor for diabetic foot infections and the
need for vitamin D supplementation in such patients for a better clinical outcome. This
could be substantiated by similar data from future studies.

Review of infectious diseases vitamin D trials – Feb 2012

Current data support vitamin D intervention for tuberculosis and viral respiratory tract
infections

Translating the role of vitamin D(3) in infectious diseases.

Crit Rev Microbiol. 2012 Feb 5.
Khoo AL, Chai L, Koenen H, Joosten I, Netea M, van der Ven A.
Radboud University Nijmegen Medical Center, Department of Laboratory Medicine,
Laboratory Medical Immunology , Nijmegen , Netherlands.

Vitamin D(3) affects both the innate as well as adaptive immune responses.
Epidemiological studies have established that vitamin D(3) deficiency plays an important
role in tuberculosis (TB) and viral influenza prevalence as well as susceptibility to active
disease in TB. Vitamin D(3) status has been associated with the clinical course of HIV
infection and drug interaction with anti-retroviral therapy.

This article reviews the immunomodulatory capacity of vitamin D(3) and examines the
impact of vitamin D(3) supplementation as a preventive or therapeutic intervention with
the intent to uncover its potential therapeutic application in infectious diseases and to
identify novel areas for future research.

We present a review of randomized, controlled clinical studies conducted in humans
which included assessment of the immune function or clinical outcome as study end
points.

Current data support vitamin D(3) supplementation as risk-modifying intervention
in tuberculosis and viral respiratory tract infection, but the optimal dosage
regimen remains to be determined.

However, to date the knowledge on its role in fungal infection and sepsis is limited
although a potential benefit could be harnessed from its ability to curtail the
unrestrained pro-inflammatory response and therefore prevent excessive collateral
tissue damage.

The Lancet, Volume 379, Issue 9824, Pages 1373 - 1375, 14 April 2012

This article can be found in the following collections: Global Health; Public
Health; Infectious Diseases (Paediatric infections); Nutrition &
Metabolism (Undernutrition, Nutrition & metabolism-other); Paediatrics (Paediatric
infections, Paediatric respiratory medicine); Respiratory Medicine (Paediatric respiratory
medicine)

Published Online: 10 April 2012

Bolus-dose vitamin D and prevention of childhood pneumonia

Adrian R Martineau a

Vitamin D deficiency is highly prevalent in children in southern Asia,1 where an
association with susceptibility to pneumonia—the leading cause of child mortality in the
region2—has been reported.3, 4 Oral boluses of vitamin D induce large and rapid rises in
circulating concentrations of calcifediol, the major circulating vitamin D metabolite,
which supports broad-spectrum innate immune responses to microbes in vitro.5 The
case to undertake trials of bolus-dose vitamin D supplementation for pneumonia
prevention in this setting is therefore compelling. In The Lancet, Semira Manaseki-
Holland and colleagues6 report results of such a trial, but show no beneficial effect. They
randomly assigned 3046 infants aged 1—11 months in Kabul, Afghanistan, to receive a
quarterly dose of 2·5 mg (100 000 IU) colecalciferol or placebo over 18 months. Vitamin
D supplementation did not affect the incidence of first episodes of pneumonia (incidence
rate ratio 1·05, 95% CI 0·88—1·25); indeed, an excess of repeat episodes of pneumonia
was recorded in the intervention group (0·06 vs 0·04 episodes per child per year).

Does this result spell the end for the hypothesis that vitamin D supplementation might
prevent pneumonia? Certainly the trial has important strengths: it is the largest to
assess this question published so far; power calculation assumptions regarding low
baseline vitamin D status and high pneumonia incidence in the study population were
fulfilled; and the dose of vitamin D given was generous. The interpretation that the
hypothesis is flawed must therefore be considered. However, the possibility remains that
investigation of a different dosing regimen of vitamin D in a different population might
yet yield a positive result.

The first reason to consider this possibility relates to the pharmacokinetics of calcifediol
response to quarterly administration of large bolus doses of vitamin D to infants. This
resulted in a rapid increase in circulating calcifediol concentrations—to
supraphysiological concentrations in some cases—with a subsequent slow decline to

concentrations similar to those recorded in unsupplemented children.6 Such peaks and
troughs could have potentially deleterious effects on the immune response:
concentrations of calcifediol greater than 140 nmol/L have been associated with
impaired immunity to infection,6 possibly related to the fact that vitamin D can suppress
adaptive responses to infection as well as boosting innate responses.7 Moreover, chronic
exposure to falling calcifediol concentrations has been postulated to cause an imbalance
between the activity of enzymes that synthesise and catabolise calcitriol in extra-renal
tissues, resulting in reduced concentrations of this active metabolite at sites of
disease.8 Either or both of these events could have contributed to the excess of
recurrent pneumonia recorded in the intervention group of the study. Giving lower doses
of vitamin D more often could induce sustained elevation of calcifediol concentrations
into the physiological range; this might have more favourable effects on immune
function.

The second issue to be considered relates to the generalisability of study results.
Malnutrition was common in the study population: more than one in six participants
had Z scores of weight-for-age of less than −2. Participants might therefore have been
at high risk of deficiencies in other micronutrients such as calcium and vitamin A, both of
which could modify effects of vitamin D supplementation; results of this study cannot
necessarily be applied to better nourished populations. Caution should also be exercised
in extrapolating results of this study to older children: pulmonary expression of pattern
recognition receptors is reduced in early life, and responses to their ligation are
attenuated.9 The ability of calcifediol to support innate antimicrobial responses in vitro is
dependent on the expression of such receptors;5 consequently vitamin D
supplementation might be more effective at enhancing immune function in older children
than in infants.

A third explanation for the lack of benefit reported in this trial relates to the possibility
that a subgroup of participants might have benefited from vitamin D supplementation,
but that this effect was obscured by a larger group of less responsive participants.
Protective effects might have been restricted to those with profound deficiency, as
recently reported in a trial of vitamin D supplementation in adults with chronic
obstructive pulmonary disease;10 alternatively, genetic variation in pathways of vitamin
D metabolism, transport, or signalling could have modified the effects of vitamin D
status on immunity to respiratory pathogens, as previously shown for
tuberculosis.11, 12 Understanding such effect modification has clinical relevance where
resources are sufficient to establish the phenotype and genotype of patients in detail,
but they are of more academic interest in low-resource settings where incidence of
childhood pneumonia is highest. Doing a pragmatic trial to assess effectiveness of bolus
vitamin D dosing in a population with high prevalence of deficiency and high incidence of

pneumonia was therefore a logical point of departure, and the negative outcome of this
study is important—not because it definitively excludes a role for vitamin D
supplementation in pneumonia prevention, but because it informs the design of future
studies. Further trials of more frequent dosing regimens in other age groups with lower
rates of malnutrition, characterising potential effect modifiers such as baseline vitamin D
status and genetic factors, are now indicated.

I am supported by a National Institute of Health Research (NIHR) programme grant on
vitamin D supplementation to prevent acute respiratory illness. I declare that I have no
conflicts of interest.

References

1 Arabi A, El Rassi R, El-Hajj , Fuleihan G. Hypovitaminosis D in developing countries—prevalence, risk factors and outcomes. Nat

Rev Endocrinol 2010; 6: 550-561. CrossRef | PubMed

2 Black RE, Cousens S, Johnson HL, et al. Global, regional, and national causes of child mortality in 2008: a systematic

analysis.Lancet 2010; 375: 1969-1987. Summary | Full Text | PDF(1713KB) | CrossRef | PubMed

3 Wayse V, Yousafzai A, Mogale K, Filteau S. Association of subclinical vitamin D deficiency with severe acute lower respiratory

infection in Indian children under 5 y. Eur J Clin Nutr 2004; 58: 563-567. CrossRef | PubMed

4 Roth DE, Shah R, Black RE, Baqui AH. Vitamin D status and acute lower respiratory infection in early childhood in Sylhet,

Bangladesh. Acta Paediatr 2010; 99: 389-393. CrossRef | PubMed

5 Liu PT, Stenger S, Li H, et al. Toll-like receptor triggering of a vitamin D-mediated human antimicrobial

response. Science2006; 311: 1770-1773. CrossRef | PubMed

6 Manaseki-Holland S, Maroof Z, Bruce J, et al. Effect on the incidence of pneumonia of vitamin D supplementation by quarterly

bolus dose to infants in Kabul: a randomised controlled superiority trial. Lancet 201210.1016/S0140-6736(11)61650-4. published

online April 10. PubMed

7 Nielsen NO, Skifte T, Andersson M, et al. Both high and low serum vitamin D concentrations are associated with tuberculosis: a

case-control study in Greenland. Br J Nutr 2010; 104: 1487-1491. CrossRef | PubMed

8 Vieth R. How to optimize vitamin D supplementation to prevent cancer, based on cellular adaptation and hydroxylase

enzymology. Anticancer Res 2009; 29: 3675-3684. PubMed

9 Levy O. Innate immunity of the newborn: basic mechanisms and clinical correlates. Nat Rev Immunol 2007; 7: 379-390. PubMed

10 Lehouck A, Mathieu C, Carremans C, et al. High doses of vitamin D to reduce exacerbations in chronic obstructive pulmonary

disease: a randomized trial. Ann Intern Med 2012; 156: 105-114. PubMed

11 Martineau AR, Leandro AC, Anderson ST, et al. Association between Gc genotype and susceptibility to TB is dependent on vitamin

D status. Eur Respir J 2010; 35: 1106-1112. CrossRef | PubMed

12 Martineau AR, Timms PM, Bothamley GH, et al. High-dose vitamin D3 during intensive-phase antimicrobial treatment of

pulmonary tuberculosis: a double-blind randomised controlled trial. Lancet 2011; 377: 242-250

Vit D supplementation cuts respiratory infection risk
ANI Aug 21, 2012, 01.06PM IST

(Vitamin D supplementation…)
Daily intake of vitamin D supplement can reduce the risk of respiratory infections such
as colds or flu among children in winter, researchers have suggested.
In a study conducted in Mongolian schoolchildren, an international research team found
that daily vitamin D supplementation decreased the risk of respiratory infections among
children who had low blood levels of vitamin D at the start of the study.
"Our randomized controlled trial shows that vitamin D has important effects on infection
risk," said Carlos Camargo, MD, of Massachusetts General Hospital (MGH), the study's
corresponding author.
"In almost 250 children with low blood levels of vitamin D during winter, we found that
taking a daily vitamin D supplement cut in half the risk of a respiratory infection,"
Camargo stated.
Several recent investigations have suggested that vitamin D - best known for its role in
the development and maintenance of strong bones - has additional important roles,
including in immune function.
Since vitamin D is naturally produced by the body in response to sunlight, maintaining
adequate levels in winter is particularly challenging in areas such as the northern U.S.
andCanada that have significant seasonal variations in daily sunlight.
The current study analyzed data from the Blue Sky Study, conducted in
Ulaanbaatar,Mongolia, by a team led by Harvard investigators in collaboration with local
health researchers.
Mongolians are known to be at high risk for vitamin D deficiency, especially during
winter, and the Blue Sky Study followed schoolchildren, all of whom were found to have
low blood levels of 25-hydroxyvitamin D (25OHD), which is considered the best measure
of vitamin D status, at the study''s outset.
In the current study, Camargo and colleagues compared the number of winter
respiratory infections among a group of children who received daily doses of vitamin D
added to locally produced milk with that of a control group receiving the same milk
without added vitamin D.
Based on reports from their parents, the children receiving vitamin D had about half the
incidence of respiratory infections that the control group had.
"Our study design provides strong evidence that the association between low vitamin D
and respiratory infections is causal and that treating low vitamin D levels in children with
an inexpensive and safe supplement will prevent some respiratory infections," says
Camargo, a professor of Medicine at Harvard Medical School.
The findings will appear in the journal Pediatrics.

Original Investigation | February 2009

Association Between Serum 25-Hydroxyvitamin D Level and Upper Respiratory
Tract Infection in the Third National Health and Nutrition Examination
Adit A. Ginde, MD, MPH; Jonathan M. Mansbach, MD; Carlos A. Camargo, Jr, MD, DrPH

Arch Intern Med. 2009;169(4):384-390.

ABSTRACT
Background Recent studies suggest a role for vitamin D in innate immunity, including
the prevention of respiratory tract infections (RTIs). We hypothesize that serum 25-
hydroxyvitamin D (25[OH]D) levels are inversely associated with self-reported recent
upper RTI (URTI).
Methods We performed a secondary analysis of the Third National Health and Nutrition
Examination Survey, a probability survey of the US population conducted between 1988
and 1994. We examined the association between 25(OH)D level and recent URTI in
18 883 participants 12 years and older. The analysis adjusted for demographics and
clinical factors (season, body mass index, smoking history, asthma, and chronic
obstructive pulmonary disease).
Results The median serum 25(OH)D level was 29 ng/mL (to convert to nanomoles per
liter, multiply by 2.496) (interquartile range, 21-37 ng/mL), and 19% (95% confidence
interval [CI], 18%-20%) of participants reported a recent URTI. Recent URTI was
reported by 24% of participants with 25(OH)D levels less than 10 ng/mL, by 20% with
levels of 10 to less than 30 ng/mL, and by 17% with levels of 30 ng/mL or more
(P < .001). Even after adjusting for demographic and clinical characteristics, lower
25(OH)D levels were independently associated with recent URTI (compared with
25[OH]D levels of ≥30 ng/mL: odds ratio [OR], 1.36; 95% CI, 1.01-1.84 for <10 ng/mL
and 1.24; 1.07-1.43 for 10 to <30 ng/mL). The association between 25(OH)D level and
URTI seemed to be stronger in individuals with asthma and chronic obstructive
pulmonary disease (OR, 5.67 and 2.26, respectively).
Conclusions Serum 25(OH)D levels are inversely associated with recent URTI. This
association may be stronger in those with respiratory tract diseases. Randomized
controlled trials are warranted to explore the effects of vitamin D supplementation on
RTI.

Review

The role of vitamin D in pulmonary disease: COPD, asthma, infection, and
cancer
Christian Herr1,3, Timm Greulich1, Rembert A Koczulla1, Silke Meyer2, Tetyana
Zakharkina1,3, Meret Branscheidt1, Rebecca Eschmann1 and Robert Bals1,3*
 *Corresponding author: Robert Bals robert.bals@uks.eu
Author Affiliations
1
Department of Internal Medicine, Division for Pulmonary Diseases, Philipps-
Universtät Marburg, 35043 Marburg, Germany
2
Department of Internal Medicine, Division of Endocrinology & Diabetology,
Department of Internal Medicine, University Hospital Marburg, 35043 Marburg,
Germany
3
Department of Pulmonology, University of the Saarland, 66421 Homburg Saar,
Germany
For all author emails, please log on.
Respiratory Research 2011, 12:31 doi:10.1186/1465-9921-12-31

Abstract

The role of vitamin D (VitD) in calcium and bone homeostasis is well described. In the
last years, it has been recognized that in addition to this classical function, VitD
modulates a variety of processes and regulatory systems including host defense,
inflammation, immunity, and repair. VitD deficiency appears to be frequent in
industrialized countries. Especially patients with lung diseases have often low VitD serum
levels. Epidemiological data indicate that low levels of serum VitD is associated with
impaired pulmonary function, increased incidence of inflammatory, infectious or
neoplastic diseases. Several lung diseases, all inflammatory in nature, may be related to
activities of VitD including asthma, COPD and cancer. The exact mechanisms underlying
these data are unknown, however, VitD appears to impact on the function of
inflammatory and structural cells, including dendritic cells, lymphocytes, monocytes, and
epithelial cells. This review summarizes the knowledge on the classical and newly
discovered functions of VitD, the molecular and cellular mechanism of action and the
available data on the relationship between lung disease and VitD status.

Keywords:
Vitamin D; mortality; asthma; COPD; respiratory tract infection; immunity

Review

VitD supplementation appears to be correlated with decreased total mortality [1]. In the
early 1920s a group of scientists independently discovered that irradiating of certain
foods with ultraviolet light renders them antirachitic [2,3] and in 1922 Elmer V.
McCollum identified an antirachitic substance in cod liver oil and called it "vitamin D" [4].
While the role of VitD in calcium and bone homeostasis has been well described, its
activities on other physiological and pathophysiological processes have been recognized
only in the last years. Epidemiological data suggest that several lung diseases, all

inflammatory in nature, may be related to activities of VitD. VitD deficiency might have a
role in the development of these diseases. The underlying mechanisms how VitD
metabolisms could be linked to the pathophysiology of these diseases are often complex
and not fully understood. This review summarizes the role of VitD in lung diseases.

Evolutionary aspects

VitD and its receptors are found throughout the animal kingdom and are often linked to
bone and calcium metabolisms. The fact that precursors of VitD are found in ancient
organisms like krill and phytoplankton that existed unchanged for at least 750 million
years [5] highlights its importance in physiologic and homeostatic processes.
Variants of VitD and its receptors have been identified in higher terrestrial vertebrates
like humans[6], rodents [7], birds [8], amphibia [9], reptiles [10], as well as in
zebrafish [11]. These animals possess a calcified skeleton and depend on a functional
VitD hormone system for calcium and phosphorus homeostasis. Surprisingly, functional
VitD receptors (VDRs) have also been found in lampreys, an ancient vertebrate that
lacks a calcified skeleton [12]. VDRs were also identified in animals with a naturally
impoverished VitD status like the subterranean mole rat [13] and a frugivorous
nocturnal mammal, the Egyptian fruit bat Cavaleros [14]. VitD precursors have been
found in ancient organisms like phytoplankton and zooplankton, some of which exist
unchanged for at least 750 million years [5,15]. Functional VitD hydroxylases have also
been characterized in bacteria like strains of actinomyces [16,17]
and streptomyces [18,19]. The precursors of VitD in those organisms may function as a
natural sunscreen to protect the host against UV-radiation, since the absorption spectra
of pro-vitamin D and their photoproducts overlap with the absorption maxima of DNA,
RNA, and proteins [20].

Role of VitD in bone metabolism

VitD, which is photosynthesized in the skin or has been derived from nutrition, is
metabolized two times, before it mediates its calcemic effects by binding to the nuclear
VitD receptor (VDR) [21,22](Figure 1). The metabolizing enzymes belong to a group of
cytochrome P450 hydroxylases, which can be found in eukaryotes, bacteria, fungi and
plants. In the human liver, the first hydroxylation of VitD on C-25 is performed by
mitochondrial 25-hydroxylase enzymes (gene names: CYP27A1[23] and/or
CYP2R1 [24]) that both belong to the cytochrome P450 family. The inactive 25-(OH)-
vitamin D3 (25-(OH)D3) metabolite is further hydroxylated at position 1α by the
mitochondrial cytochrome P450 enzyme 25-hydroxyvitamin-D-1α-hydroxylase (gene
name: CYP27B1) and converted to the bioactive 1α,25-dihydroxyvitamin D(1,25-
(OH)2D3). This latter step is mainly localized to the proximal kidney tubule [25],
however, many other cell types, including lung epithelial cells, are capable to perform
this reaction [26-29]. The serum concentration of 25-(OH)D3 reflects the organism's VitD
supply [30]. In the blood, VitD and the inactive, relatively stable 25-(OH)D3 metabolite
are bound in 99% to the vitamin D binding protein (DBP) [31]. DBP polymorphisms (Gc
phenotype) are related to the DBP concentration and VitD status [32]. The 1α-
hydroxylation of 25-(OH)D3 is upregulated by parathyroid hormone (PTH), calcitonin, low
calcium- and phosphate levels as well as by estrogen, prolactin and growth
hormone [33]. Calcitonin, cortisol, high phosphate levels and 25-(OH)D3 suppress the

25-hydroxyvitamin D-1α-hydroxylase activity [34]. 1,25-(OH)2D3 itself works as its own
negative feedback regulator by induction of the expression of a 24-hydydroxylase
(CYP24A1). Further, 1,25-(OH)2D3 decreases the production and secretion of PTH. PTH
synthesis and secretion is induced by decreased serum calcium levels, which are
detected by the calcium sensing receptor of the parathyroid gland. PTH effects renal
tubular reabsorption of calcium, renal production of 1,25-(OH)2D3 and promotes
osteoclastogenesis [35].

Figure 1. Metabolism and effects of VitD. VitD can be obtained from
food or from synthesis in the skin under exposure to light. The precursor is hydroxylated
cytochrome P450 25-hydroxylase enzymes CYP27A1 and/or CYP2R1 and subsequently
by the cytochrome P450 enzyme 25-hydroxyvitamin D-1α-hydroxylase (CYP27B1) and
converted to the bioactive 1,25-(OH)2D3, which has role in Ca and bone metabolism and,
in addition, in several other biological processes. Of note, bioactive 1,25-(OH)2D3 can
also be generated in lung epithelia cells and monocytes/macrophages.
1,25-(OH)2D3 is essential for the development and maintenance of the growth plate,
chondrocyte growth, and the mineralised bone [21]. 1,25-(OH)2D3 modulates the
osteoclastogenesis by regulation of the receptor activator of nuclear factor kappa B
(RANK), RANK ligand (RANKL) and the soluble receptor osteoprotegerin (OPG) [36]. It
increases the expression of RANKL on the osteoblast surface, which supports maturation
of progenitor and mature osteoclasts, and it inhibits OPG expression, which binds RANKL
and prevents RANK mediated osteoclastogenesis [37].
VitD deficiency causes the development of an imbalanced calcium- and phosphate-
homeostasis and the occurrence of the bone diseases osteopenia, osteoporosis, rickets,
and osteomalacia with a subsequently increased fracture risk [38]. The 25-(OH)D3 serum
concentration is directly associated with bone mineral densitys. VitD deficiency has
several causes including inadequate sun exposure (and loss of functional capacity of the
skin especially in the elderly), limited renal and hepatic function or insufficient intestinal
resorption [39]. In VitD deficiency, the feedback on the PTH gene promoter is lacking
resulting in parathyroid hyperplasia, hyperparathyroidism, and a mineralization defect of
the bone.
1,25-(OH)2D3 regulates many target genes by binding to the VDR: approximately 3% of
the mouse and human genome is regulated via the VitD pathway [40]. As non-genomic
action of VitD in chondrocytes, it increases the membrane-lipid turnover, prostaglandin
production and protease activity, leading to bone matrix modification and calcification.
Additionally to the expression of VDR in bone and multiple tissues, the presence of 1α-
hydroxylase in cells of several extrarenal tissues such as bone as well as skin, prostate,
the respiratory and gastrointestinal tract, strongly suggest that VitD impacts on
processes beyond the calcium and bone metabolism.

Role of VitD in immunity and host defense

More than a century ago (1849), the British physician C.J.B. Williams described the use
of cod liver oil in the treatment of tuberculosis. He reported that among his tuberculosis
patients, 206 out of 234 showed a "marked and unequivocal improvement" after
treatment with cod liver oil [41]. Since then manifold functions of VitD have been

discovered, indicating that VitD regulates many cellular processes and is potentially
involved in the development of many diseases. Since the discovery of VDRs in a variety
of cells of the adaptive immune system such as B- and T-lymphocytes [42,43], there
have been numerous reports about the immunomodulatory activities of VitD.
Cellular studies revealed that VitD modulates the activity of various defense and immune
cells including monocytes, macrophages, lymphocytes, or epithelial cells:

• Monocytes/macrophages: Low serum concentrations of VitD in patients with rickets
correlate with decreased phagocytic activity of macrophages [44] that could be reversed
by supplementation with 1,25-(OH)2D3 [45]. Antimicrobial activity of macrophages
against M. tuberculosis is increased in the presence of 25-(OH)D3 after stimulation with
mycobacterial ligands. Mycobacterial activation of toll-like receptor-2 (TLR-2) leads to an
increased expression of VDR and CYP27B that results in an increased conversion of 25-
(OH)D3 to 1,25-(OH)2D3 and subsequent expression of the antimicrobial peptide
cathelicidin via VDR [46,47].
• B lymphocytes: It has been shown that 1,25-(OH)2D3 plays a role in B cell homeostasis
by the inhibition of proliferation and induction of apoptosis of activated B cells [48].
1,25-(OH)2D3inhibits the differentiation of B lymphocytes to plasma cells and memory B
cells. These mechanisms may contribute to the pathogenesis of B-lymphocyte related
diseases like systemic lupus erythematosus (SLE). Patients with SLE have significant
lower serum concentration of both 25-(OH)D3 and 1,25-(OH)2D3 [49,50].
• T lymphocytes: A well-established function of VitD within the adaptive immune system
is its ability to modulate T lymphocyte proliferation and function. The biologically active
1,25-(OH)2D3inhibits proliferation of TH lymphocytes [51] and shifts the expression of
cytokines from a TH1 based response towards a TH2 based profile [52,53]. Although
1,25-(OH)2D3 might be able to involve direct effects on T lymphocytes through the
support of differentiation of regulatory T cells, current data indicate that 1,25-
(OH)2D3 exerts its influence on the adaptive immune response by modulating the
functions of dendritic cells (DCs). Regulatory T cells seem to be activated by VitD with
skewing of the Th1/Th2 balance towards Th2 [54]. Of note, there is evidence for and
against the role of VitD in Th2 biased diseases [55], which will be discussed in more
detail in the asthma section below.
• Dendritic cells: The response of DCs to 1,25-(OH)2D3 is restricted to myeloic DC, that
express a different set of TLRs and cytokines than plasmacytoic DCs, which showed no
tolerogenic response to 1,25-(OH)2D3 [56]. 1,25-(OH)2D3 inhibits the maturation of DCs
and enhances the expression of cytokines like IL-10, thereby 1,25-(OH)2D3 induces
tolerance through the suppression of T H1 lymphocyte development and the induction of
regulatory T cells [57].
• Epithelial cells: Airway epithelial cell express enzymes of the VitD metabolism and are
capable to convert the precursor 25-(OH)D3 into the active 1,25-(OH)2D3 from [29,58].
They are an important source of 1,25-(OH)2D3 that induces the expression of cathelicidin
or CD14 by cells of the innate immune system. 1,25-(OH)2D3 converted by airway
epithelial cells is able to modulate the inflammatory profile after a viral infection by
blocking the poly(I:C) induced chemokine and cytokine production while maintaining the
antiviral activity [28,59]. As epithelial cells are primary targets of respiratory pathogens
and cathelicidin has antibacterial and antiviral activity, a seasonal decrease of VitD-
dependent epithelial host defense could contribute to increased numbers of lower
respiratory tract infection (RTI) during winter.

Roles of VitD in pulmonary diseases

VitD has complex effects on pulmonary cell biology and immunity with impact on
inflammation, host defense, wound healing, repair, and other processes. While the
knowledge on direct mechanistic links between VitD and lung diseases is limited, a
number of epidemiological and experimental are available that highlight the relevance of
this connection.

a) Asthma
A connection between VitD status and asthma has been considered since many years.
VitD deficiency has been blamed as one cause of increased asthma prevalence in the last
decades[60]. VDR variants were found to be associated with asthma in patient
cohorts [61]. A recent clinical investigation showed that high VitD levels are associated
with better lung function, less airway hyperresponsiveness and improved glucocorticoid
response [62]. A population-based study suggested that lower VitD levels are associated
with increased requirements for inhaled corticosteroids in children [63]. Vitamin D
insufficiency is common in this children with mild-to-moderate persistent asthma and is
associated with higher odds of severe exacerbation [64]. Epidemiologic studies have also
shown that maternal VitD intake during pregnancy protects from wheezing in
childhood [65,66]. In contrast, also data exist that children whose mothers had high
VitD levels in pregnancy had an increased risk of eczema and asthma [67], suggesting
that the time point of Vit D supplementation seems to determine the susceptibility to
atopic disease. On the experimental level in a murine asthma model, the VDR is
necessary for the development of an allergic airway inflammation [68].
The underlying mechanisms how VitD modulates the pathogenesis of asthma are not
clear. VitD may protect from developing respiratory infections that could serve as trigger
for a deterioration of asthma [69]. VitD may also modulate the function of various
immune cells as outlined above. Interestingly, application of VitD is potentially capable
to overcome the poor glucocorticoid responsiveness in severe asthmatics by
upregulation of IL-10 production from CD4+ T cells [70].
b) Chronic obstructive lung disease (COPD)
The connection between VitD status and COPD has attracted attention in the recent
months. This is based on data from observational studies that determined levels of VitD
in COPD patients. Black and colleagues examined data from the NHANES III data set
(cross-sectional survey of 14091 adults in the US). After adjustment for potential
confounders, a strong relationship between serum levels of VitD and lung function
(FEV1 and FVC) was found [71]. Although a significant correlation with airway
obstruction could not be found, the observed dose-response relationship may suggest a
causal link [72]. A number of studies have reported on 25-(OH)D3 levels in COPD
patients. Forli et al. found VitD deficiency (in this study defined as below 20 ng/ml) in
more than 50% of a cohort waiting for lung transplantation [73]. In an outpatient study
on patients with COPD in Denmark, 68% of the participants had osteoporosis or
osteopenia [74]. A recent study showed that VitD deficiency is highly prevalent in COPD
and correlates with variants in the VitD binding gene [75]. There are several factors that
could account for VitD deficiency in COPD patients: Poor diet, a reduced capacity of
aging skin for VitD synthesis, reduced outdoor activity and therefore sun exposure, an
increased catabolism by glucocorticoids, impaired activation because of renal
dysfunction, and a lower storage capacity in muscles or fat due to wasting [76]. Many

steps of the VitD pathway (intake, synthesis, storage, metabolism) can potentially be
disturbed in COPD patients.
A single nucleotide polymorphism (SNP) of the DBP was shown to be associated with a
decreased risk of COPD by a mechanism that is unclear [77]. Similar SNPs in the gene
coding for DBP may influence the level of circulating 25-(OH)D3 and 1,25-
(OH)2D3 [32,78]. Therefore it has been hypothesized that their protective role might be
mediated by the bioavailability of 1,25-(OH)2D3[79].
The mechanisms that link VitD biology with the development of COPD are largely
speculative:

1) The association of VitD deficiency and reduced lung function could depend on the
calcemic effects of VitD. The vital capacity and total lung capacity was found to decline
with an increasing number of thoracic vertebral fractures as a direct consequence of VitD
deficiency [80]. Nuti et al. observed 3030 ambulatory COPD patients and found a strong
association between COPD severity and fractures [81]. Kyphosis related to osteoporosis
caused limitation in rib mobility and inspiratory muscle function and correlated with a
reduction in FEV1 and FVC [82]. The altered properties of the thoracic skeleton could
result in failure of the respiratory muscles contributing to the pathophysiology of COPD.
2) VitD deficiency could result in altered host defense of the lung with subsequent
growth of an abnormal flora that triggers inflammation. Acute exacerbations of COPD
are an important cause of hospitalization and lead to a faster decline in FEV 1 [83].
Exacerbations are triggered by viruses, bacteria, atypical strains, or a combination of
these [84-87]. Potential bacterial pathogens are detected in about 50% of
exacerbations. A therapeutic consequence would be the up-regulation of the innate
immune defense system. Wang and colleagues demonstrated that genes coding for the
antimicrobial peptide cathelicidin (LL-37/hCAP-18) are regulated by VDRE-containing
promoters [88]. In cultured monocytes, a local increase of the 1,25D3-VDR complex
stimulates the production of LL-37, resulting in an improved intracellular eradication
ofMycobacterium tuberculosis [47]. The data demonstrated that the activation of TLRs
on human monocytes triggers a microbicidal pathway that is dependent on both the
endogenous production and action of 1,25-(OH)2D3 through the VDR.
3) The effect of VitD on extracellular matrix homeostasis not only in bone tissue, but
also within the lung may have a role in COPD development. Boyan et al. found VitD to
be an autocrine regulator of extracellular matrix turnover and growth factor release via
matrix metalloproteinases[89]. Matrix metalloproteinasis-9 (MMP-9) has been shown to
be elevated in induced sputum of COPD patients and a causative role has been
suggested in the development of COPD [90]. VitD also to attenuates TNF-alpha induced
upregulation of MMP-9 in keratinocytes [91]. VitD deficiency may lead to a reduced
attenuation of MMP-9 activity resulting in enhanced degradation of lung parenchyma.
Recently, it has been recognized that COPD is a systemic disease [92] with several
closely related comorbidities [93]. Interestingly, VitD deficiency is associated with a
equivalent spectrum of diseases including coronary heart disease, cancer, inflammatory
disease and infection [76]. Comorbidities of COPD such as reduced bone mineral density
and skeletal muscle weakness[94,95] have been associated with low VitD serum
concentrations.

c) Infection
Tuberculosis
A number of candidate polymorphisms of VitD receptor (VDR) and VitD binding protein
(DBP) have been identified that modulate the development of tuberculosis [96]. The
genotype tt (detected by Taq I digestion) is associated with decreased risk of
tuberculosis. As described by Lewis et al.[97], larger studies are required to determine
whether VDR polymorphisms play a role in genetic susceptibility to tuberculosis
worldwide. In a recent meta-analysis, low serum levels of 25-(OH)D3were associated
with a higher risk of active tuberculosis. The pooled effect size was 0.68 with 95% CI
0.43 - 0.93. The authors concluded that the low VitD levels increase the risk of active
tuberculosis [98]. There are several randomized, double-blind, placebo-controlled trials
of VitD treatment in tuberculosis. In one study, 67 tuberculosis patients were
randomized to receive VitD (0.25 mg/day) or placebo during the 6 initial week of Tb
treatment [99]. A statistical significant difference in sputum conversion (i.e, the change
of detectable to no detectable Mycobacteria in the sputum) was discovered in favor of
the VitD group (100% vs. 76,7%; p = 0.002). Another trial was conducted in 192
healthy adult tuberculosis contacts in London, United Kingdom [100]. Participants were
randomized to receive a single oral dose of 2.5 mg VitD or placebo and followed up at 6
weeks. VitD supplementation significantly enhanced the ability of participants' whole
blood to restrict BCG-lux luminescence after 24 hours in vitro as compared with placebo,
but did not affect antigen-stimulated IFN-gamma secretion after 96 hours. As the innate
immune responses are mobilized more rapidly than acquired immune responses, the
authors interpreted the 24- and 96-hour results as indicators of innate and acquired
responses, respectively. They concluded that vitamin D supplementation may primarily
enhance innate responses to mycobacterial infection. Wejse et al. included 365
tuberculosis patients starting anti-tuberculotic treatment in Guinea Bissau[101]. 281
patients completed the 12 month follow-up. The intervention was 100,000 IU
cholecalciferol or placebo at inclusion and again at 5 and 8 months after start of
treatment. Reduction in TBscore and sputum smear conversion rates did not differ
among VitD and placebo treated patients. Taken those data together there seems to be
a benefit of VitD in the treatment of tuberculosis but this could not be reproduced in the
largest study so far.
Respiratory tract infections (RTI)
RTI are more common in the winter period than during summertime. Because the food
intake of VitD is insufficient, sunlight exposure is the primary determinant of VitD status
in humans, and seasonal differences in VitD level in human are well documented [76].
During the winter months, there is insufficient UV-B exposure to produce sufficient
amounts of VitD. Wintertime VitD insufficiency may explain seasonal variation in
influenza and other, mostly viral, RTIs [102]. Ginde et al. performed a secondary
analysis of the Third National Health and Nutrition Examination Survey, hypothesizing an
association between 25-(OH)D3 level and self-reported upper respiratory tract infections
(URTI) in 18883 subjects [103]. After adjusting for season, body mass index, smoking
history, asthma, and COPD, lower 25-(OH)D3 levels were independently associated with
recent URTI. In patients with respiratory tract diseases (asthma and COPD) the
association between 25-(OH)D3 level and URTI seemed to be even stronger (OR, 5.67
and 2.26, respectively). Avenell and colleagues used data from the RECORD trial (VitD in
secondary prevention of osteoporotic fractures; n = 5292) [104]. In a "per protocol"
analysis, a trend towards a benefit of VitD vs. placebo was detected, though not

statistically significant. Despite the large number of patients in these studies, restrictions
arise from the retrospective data analysis. A prospective cohort study included 800
young Finnish men serving on a military base [105]. Their serum 25-(OH)D3 was
measured in the beginning of a 6 month observational period. Subjects with low 25-
(OH)D3 levels had significantly more days of absence from duty due to respiratory
infection than did control subjects (p = 0.004). In a case control study a total of 150
children (80 cases, 70 controls) was enrolled [106]. Low serum 25-(OH)D3 (≤ 22.5
nmol/l) was associated with a significantly higher odds ratio for having severe acute
lower respiratory tract infections (p < 0.001). These studies support an role of VitD in
the development of lung infection.
However, in a recent clinical trial, Li-Ng et al. randomized 162 adults to 50 μg VitD
(2000 IU) daily or placebo for 12 weeks. Using a questionnaire they recorded the
incidence and severity of upper RTI symptoms. Although VitD serum levels increased
significantly in the VitD treated group (vs. no change in the placebo group), there was
no benefit of VitD supplementation in decreasing the incidence or severity of
symptomatic URTI [107]. This may be explained by the relatively low number of
subjects. Furthermore, the time period of 12 weeks was probably too short to show any
effect. Taken together, there is growing evidence for a protective role of VitD in the
development of RTI but high quality randomized clinical trials within a sufficiently high
number of patients and for a sufficient period of time are missing. In a recently
published trial, the supplementation of 1500 E VitD per day resulted in deceases
incidence of influenza A by 64% [69].
d) Cancer
A number of studies suggest that low levels of VitD are associated with an up to 50%
increased risk of colon, prostate, or breast cancer [76,108]. As an example, a recent
nested case-control study showed that pre-diagnostic levels of VitD are inversely
correlated with the risk of colon cancer [109]. For lung cancer, the picture is not clear at
the present time. While TaqI polymorphism of the VDR gene appears to be a risk factor
for lung cancer [110], low levels of VitD were only a cancer risk factor in subgroups, i.e.,
in women and young individuals [111]. In patients with diagnosed lung cancer, there
was no main effect of VitD level on overall survival[112]. In preclinical animal models
using carcinogen (NNK)-induced lung carcinogenesis, application of 1,25-
(OH)2D3 resulted in decreased cancer growth [113].

Conclusions

VitD has a number of activities in addition to its effect on calcium and bone homeostasis
and influences process such as immune regulation, host defense, inflammation, or cell
proliferation. VitD deficiency is potentially involved in a number of lung disease. Several
hurdles must be overcome to validate the benefit of VitD-based therapies: 1) Basic
mechanisms are not clear and the involved molecular pathways are likely difficult to
identify because VitD impacts on a variety of biological processes in parallel. 2)
Conclusive data from interventional studies are missing for many disease entities. 3)
Since VitD has been used for many years, the pharmaceutical industry might hesitate in
starting a development program. Nevertheless, the data available indicate that VitD
could be beneficial for the prevention or therapy of important lung diseases.

List of abbreviations

1,25-(OH)2D3: 1α: 25-dihydroxyvitamin D; 25-(OH)D3: D325-(OH)-vitamin D3; TLR: toll
like receptor; VitD: vitamin D;

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