1) Several studies show high rates of vitamin D deficiency and insufficiency among children with asthma. Low vitamin D levels are associated with worse asthma control, including increased exacerbations and hospitalizations. 2) Observational studies link higher maternal vitamin D intake during pregnancy to lower rates of wheezing and asthma in offspring. However, the evidence for a causal relationship is still insufficient. 3) Maintaining adequate vitamin D levels, especially during pregnancy and childhood, may help reduce asthma risk and severity by supporting lung development and function. Further research is still needed.

1. Vitamin D and Asthma
 Vitamin D
deficiency-insufficiency
 Onset of Disease
 Morbidity & Exacerbations
 Protective Mechanisms
 Summary & Conclusions
University of
Verona, Italy
Attilio Boner
attilio.boner@univr.it

2. Synthesis and Metabolism of Vitamin D.
Rosen CJ. NEJM 2011;364:248
Vitamin D is initially generated in the skin from the nonenzymatic
conversion of provitamin D3 to previtamin D3.
Dietary intake of vitamin D is usually relatively limited, since few
foods, with the exception of certain kinds of fish, contain sizable
amounts; supplements are commonly used.
Vitamin D is either stored in adipose tissue or converted in the liver by
the enzyme 25-hydroxylase to 25-hydroxyvitamin D3 (25[OH]D3), the
form that circulates in the highest concentration and reflects solar
and dietary exposure.
It is converted to the active metabolite, 1,25-dihydroxyvitamin D
(1,25[OH]2D), or calcitriol, in the kidney, although other tissues have
1α-hydroxylase enzymatic activity. The synthesis of calcitriol is
enhanced (+) by increasing levels of parathyroid hormone (PTH), which
rise in response to lower levels of serum calcium. Reduced levels of
serum phosphate can also increase (+) the production of calcitriol.
Its synthesis is suppressed (–) by the production of fibroblast
growth factor 23 (FGF-23), which is secreted by osteocytes in the
bone matrix.
Calcitriol inhibits the activity of 1α-hydroxylase (CYP27B1) and
stimulates the activity of 24-hydroxylase (CYP24R1), an enzyme that
promotes production of 24,25(OH)2D3, a vitamin D product
that is not biologically active.
In CYP2R1, CYP27B1, and CYP24R1, CYP denotes cytochrome P.

3. The 2011 report on dietary reference intakes for
calcium and vitamin D from the Institute of Medicine:
what clinicians need to know.
Ross AC, J Clin Endocrinol Metab. 2011;96:53-8.
RDA = Recommended Dietary Allowance; UL= tolerable upper intake level; c= not well defined

4. RDA = Recommended Dietary Allowance; UL= tolerable upper intake level; c= not well defined
The 2011 report on dietary reference intakes for
calcium and vitamin D from the Institute of Medicine:
what clinicians need to know.
Ross AC, J Clin Endocrinol Metab. 2011;96:53-8.
Dietary Reference
Intake
shown in Table 1
are based on dietary
requirements
using bone health as
an indicator.

5. There are several publications suggesting that vitamin D
deficiency (25-hydroxyvitamin D level <20 ng/mL) and
insufficiency (25-hydroxyvitamin D level >20 ng - <30 ng/mL) is a
pandemic affecting all populations with serious health consequences.
Vitamin D deficiency-insufficiency
 Wang TJ, Circulation 117, 503–511.
 Dobnig H, Arch Intern Med 168, 1340–1349.
 Melamed ML, Arch Intern Med 168, 1629–1637.
 Melamed ML, Arterioscler Thromb Vasc Biol 28, 1179–1185.
 Dong Y, J Clin Endocrinol Metab 95,4584–4591.
 Reis JP, Pediatrics 124, e371–e379.
 Kumar J, Pediatrics 124, e362–e370.
Sabetta JR, PlosOne 5,e11088.
 Moan J, Proc Natl Acad Sci USA 105, 668–673.

6. High Prevalence of Vitamin D Deficiency among Inner-
City African American Youth with Asthma in Washington
Freishtat J Pediatr 2010;156:948-52
 Urban African-American
(AA) youth with asthma
(=92)
 control subjects without
asthma (=21).
 25-hydroxyvitamin D
insufficiency (<30 ng/mL)
and deficiency (<20 ng/mL).
86%
% children with <30 ng/mL Vit D
Asthmatics Controls
19%
100 –
90 –
80 –
70 –
60 –
50 –
40 –
30 –
20 –
10 –
0

7. Asthma prevalence associated with geographical
latitude and regional insolation in the United States of
America and Australia. Krstić G. PLoS One. 2011;6:e18492.
Asthma prevalence vs. latitude in
metropolitan/micropolitan areas of USA
Linear regression analyses on
asthma prevalence in adult
population vs. geographical
latitude, insolation, air
temperature, and air pollution
(PM(2.5))
 97 metropolitan/micropolitan
statistical areas of the USA and
in 8 metropolitan areas of
Australia.
50°
25°

8. Asthma prevalence associated with geographical
latitude and regional insolation in the United States of
America and Australia. Krstić G. PLoS One. 2011;6:e18492.
Asthma prevalence vs. latitude in the
population of 8 major metropolitan areas of
Australia.
Linear regression analyses on
asthma prevalence in adult
population vs. geographical
latitude, insolation, air
temperature, and air pollution
(PM(2.5))
 97 metropolitan/micropolitan
statistical areas of the USA and
in 8 metropolitan areas of
Australia.
-50°
-10°

9. Vitamin D and Asthma
 Vitamin D
deficiency-insufficiency
 Onset of Disease
 Morbidity & Exacerbations
 Protective Mechanisms
 Summary & Conclusions
University of
Verona, Italy
Attilio Boner
attilio.boner@univr.it

10. Vitamin D deficiency causes deficits in lung function and
alters lung structure. Zosky GR, AJRCCM. 2011;183:1336-43.
mouse model of vitamin D
deficiency
by dietary manipulation
thoracic gas volume
standard vitamin D
sufficient diet
airway resistance tissue elastance

11. Genetic analysis of lung function in inbred mice suggests
vitamin D receptor as a candidate gene
Berndt A, Mol Genet Genomics 2011;286:237–246
Vitamin D receptor
(Vdr) knockout mice
Vdr knockout mice showed
significantly higher airway
dynamic resistance than mice
with one (i.e., heterozygous) or
both copies (i.e., wild-type) of
the Vdr.
Increase in dynamic resistance (R slope)
caused by consecutive doses of methacholine
exposure in mice deficient in Vdr (Vdr-KO)
and mice carrying one (Vdr-HET) or
two copies (Vdr-WT ) of Vdr.
P<0.05
Vdr +
Vdr +
Vdr +
Vdr -
Vdr -
Vdr -

12. 1.194 mother-child
pairs in Boston
Maternal intake of
vitamin D during
pregnancy with FFQ
Recurrent wheeze
In 3 yrs-old children of mothers in
the highest quartile of vitamin D
intake (724 IU) versus the lowest
quartile (356 IU) OR for
1 –
0
0.39
p<0.001
Maternal intake of vitamin D during pregnancy and risk
of recurrent wheeze in children at 3 y of age.
Camargo CA JrAm J Clin Nutr. 2007;85:788-95.

13. Random sample of
2000 healthy Scottish
pregnant women at
approximately 12 wk
gestation
Maternal vitamin D
intake ascertained at
32 wk of gestation
with FFQ Ever
wheeze
In 5 year old children of mothers
in the highest versus the lowest
quintiles of vit D intake OR for
1 –
0
0.48
Persistent
wheeze
Wheeze
in previous
year
0.35 0.33
Maternal vitamin D intake during pregnancy and early
childhood wheezing. Devereux G, Am J Clin Nutr. 2007;85:853

14. 596 pregnant women
Maternal 25 (OH) -
vitamin D
concentrations
measured in late
pregnancy
Atopy
In children whose mothers had a
25 (OH )-vitamin D concentration
>75 nmol/L compared to <30 nmol/L
3.26
Asthma
p=0.025
5.40
p=0.038
1 –
0
Maternal vitamin D status during pregnancy and child
outcomes. Gale CR, Eur J Clin Nutr. 2008;62:68-77.
at age 9 years
75 nmol/L = 30 ng/ml
30 nmol/L = 12 ng/ml

15. Maternal and child’s vitamin D supplement use and
vitamin D level in relation to childhood lung function:
the KOALA Birth Cohort Study
Cremers E, Thorax 2011;66:474-480
KOALA Birth Cohort
lung function at age 6-7
years (n=436)
Vitamin during pregnancy
and child’s vitamin D
supplement use were
collected through
questionnaires
no association
was found between
25-hydroxyvitamin D levels,
vitamin D supplementation in
childhood or recommended
vitamin D dosage of
≥ 10 µg/day during pregnancy
and lung function in children
aged 6-7 years.
1μg = 40 UI

16. VITAMIN D AND
ASTHMA ONSET
observational studies
Paul G AJRCCM 2011
Review article
•insufficient evidence of a
causal association between
vitamin D status and
asthma per se.
•merits further
assessment
The in utero effects of
maternal vitamin D
deficiency: how it results
in asthma and other
chronic diseases.
Weiss ST, Am J Respir Crit
Care Med. 2011;183:1286-7.
Editorial
•higher vitamin D intake in
pregnant women has been
linked to reduced rates of
wheezing and asthma in
their offspring.

17. VITAMIN D AND
ASTHMA ONSET
observational studies
Paul G AJRCCM 2011 in press
Review article
•insufficient evidence of a
causal association between
vitamin D status and
asthma per se.
•merits further
assessment
The in utero effects of
maternal vitamin D
deficiency: how it results
in asthma and other
chronic diseases.
Weiss ST, Am J Respir Crit
Care Med. 2011;183:1286-7.
Editorial
•higher vitamin D intake in
pregnant women has been
linked to reduced rates of
wheezing and asthma in
their offspring.
The knowledge that currently
over 90% of African-American pregnant women
and over 60% of white pregnant women are
vitamin D–deficient or insufficient and the
knowledge of the multiple negative effects of
vitamin D deficiency-insufficiency early in life
suggest the opportunity to evaluate vitamin D
serum level during pregnancy and
appropriate supplementation in deficient
or insufficient mothers
> 20 ng/mL and < 50 ng/mL
ideal level ?

18. Vitamin D and Asthma
 Vitamin D
deficiency-insufficiency
 Onset of Disease
 Morbidity & Exacerbations
 Protective Mechanisms
 Summary & Conclusions
University of
Verona, Italy
Attilio Boner
attilio.boner@univr.it

19.  25–hydroxyvitamin D
levels
 616 asthmatic children
 Vitamin D levels
deficient (<20 ng/ml),
insufficient
(≥20 and <30 ng/ml), and
sufficient (≥30 ng/ml)
Vitamin D levels were significantly
and inversely associated with:
1) total IgE and eosinophil count
2) any hospitalization in the previous
year (p=0.03),
3) any use of anti-inflammatory
medications in the previous year
(p=0.01),
4) increased airway responsiveness
(p = 0.05).
Serum Vitamin D Levels and Markers of Severity
of Childhood Asthma in Costa Rica
Brehm Am J Respir Crit Care Med 2009;179:765

20. Distribution of serum vitamin D in children in Costa Rica
Serum Vitamin D Levels and Markers of Severity
of Childhood Asthma in Costa Rica
Brehm Am J Respir Crit Care Med 2009;179:765
28% children
with
vit D <30ng/mL
(deficient-
insufficient)
sufficient
levels

21. 100 –
90 –
80 –
70 –
60 –
50 –
40 –
30 –
20 –
10 –
0
% asthmatic children with a
desiderable level of Vitamin D
(at least 30 to 40 ng/mL)
9.3%
Verona = 45°
Vitamin D Serum Levels and Markers of Asthma Control
in Italian Children Chinellato J Pediatr 2011;158:437
75 asthmatic children
25-hydroxyvitamin D
Spirometry
asthma control, according
to GINA guidelines and with
Childhood Asthma Control
Test

22. 75 asthmatic children
25-hydroxyvitamin D
Spirometry
asthma control, according
to GINA guidelines and with
Childhood Asthma Control
Test
individual data of vitamin D serum
levels in relationship with FVC % pred
r= 0.29 p=0.0013
Vitamin D Serum Levels and Markers of Asthma Control
in Italian Children Chinellato J Pediatr 2011;158:437

23. 75 asthmatic children
25-hydroxyvitamin D
Spirometry
asthma control, according
to GINA guidelines and with
Childhood Asthma Control
Test
Vitamin D Serum Levels and Markers of Asthma Control
in Italian Children Chinellato J Pediatr 2011;158:437
p=0.054
p=0.054

24. 75 asthmatic children
25-hydroxyvitamin D
Spirometry
asthma control, according
to GINA guidelines and with
Childhood Asthma Control
Test
r=0.29 p<0.01
Vitamin D Serum Levels and Markers of Asthma Control
in Italian Children Chinellato J Pediatr 2011;158:437

25. 45 children with
intermittent asthma
25-hydroxyvitamin D
baseline FVC, FEV1
∆FEV1 after a
standardized exercise
challenge
mean 25-hydroxyvitamin D (ng/mL)
30 –
20 –
10 –
0
∆FEV1≥10%
p=0.0002
∆FEV1<10%
23.5
16.2
Vitamin D Serum Levels and Lung Function and
Exercise Induced Bronchoconstriction In Children With
Intermittent Asthma. Chinellato I, ERJ 2011;37:1366

26. Vitamin D Serum Levels and Lung Function and
Exercise Induced Bronchoconstriction In Children With
Intermittent Asthma. Chinellato I, ERJ 2011;37:1366
Relationship between serum
vitamin D levels and change
FEV1 after exercise challenge
Relationship between serum vitamin D
serum level and
a) FVC and b) FEV1 % pred.
r=0.48; p=0.001
r=0.34; p=0.037
r=0.32; p=0.037

27. Relationship Between Serum Vitamin D, Disease Severity
and Airway Remodeling in Children with Asthma.
Gupta A, Am J Respir Crit Care Med. 2011;184:1342
86 children (mean age 11.7 years),
36 with severe, therapy resistant
asthma (STRA),
26 moderate asthmatics (MA)
24 non-asthmatic controls.
Serum 25-hydroxyvitamin D
(25[OH]D3)
Median 25[OH]D3 levels nmol/L
28.0
STRA
p<0.001
60 -
50 –
40 –
30 –
20 –
10 –
0
MA CONTROLS
42.5
56.5
11.2 ng/mL
17.0 ng/mL
22.6 ng/mL
p<0.001
p=0.09

28. 86 children (mean age 11.7 years),
36 with severe, therapy resistant
asthma (STRA),
26 moderate asthmatics (MA)
24 non-asthmatic controls.
Serum 25-hydroxyvitamin D
(25[OH]D3)
There was a significant negative correlation
between serum 25[OH]D3 and volume
fraction of Airway Smooth Muscle
(r= -0.6, p-0.008)
Vv (smooth muscle (SM)/SM +
submucosa) =
Volume fraction of smooth muscle
indexed to volume of submucosa tissue
Relationship Between Serum Vitamin D, Disease Severity
and Airway Remodeling in Children with Asthma.
Gupta A, Am J Respir Crit Care Med. 2011;184:1342

29. Serum vitamin D levels and severe asthma exacerbations
in the Childhood Asthma Management Program study
Brehm JACI 2010;126:52
OR for any hospitalization or
emergency department visit
1.5
2.0 –
1.5 –
1.0 –
0.5 –
0
p=0.01
In Vit D insufficiency
(<30 ng/ml) at baseline
 25-hydroxyvitamin D levels
in sera in a retrospective
longitudinal study.
 Follow-up: 4 years
 1024 children with mild-
to-moderate persistent
asthma at the time of
enrollment in CAMP study.

30. Serum vitamin D levels and severe asthma exacerbations
in the Childhood Asthma Management Program study
Brehm JACI 2010;126:52
OR for severe asthma exacerbation
(hospitalization or ED visit)
1
2.0 –
1.5 –
1.0 –
0.5 –
0
ICS treatment
Vit D sufficient
1.7 1.7
2
+
+
+
-
-
+
-
-

31. Vitamin D supplementation in children may prevent
asthma exacerbation triggered by acute respiratory
infection. Majak P, J Allergy Clin Immunol 2011;127:1294-6.
48 children (5-18 yrs)
with newly diagnosed
asthma and sensitive only
to house dust mites
budesonide 800 µg/d
administered as a dry
powder and vitamin D
placebo
(steroid group, n = 24), or
budesonide 800 µg/d and
vitamin D3-500 IU
(steroid + vit D group n=24).
Follow-up: 6 months

32. Vitamin D and Asthma
 Vitamin D
deficiency-insufficiency
 Onset of Disease
 Morbidity & Exacerbations
 Protective Mechanisms
 Summary & Conclusions
University of
Verona, Italy
Attilio Boner
attilio.boner@univr.it

33. HOW COULD VITAMIN D PROTECT
AGAINST ASTHMA MORBIDITY?
Antiviral Properties
•Airway epithelial cells can
hydroxylate 25(OH)D to its active
form (1,25 (OH)2D3), leading to
increased differentiation and
recruitment of macrophages,
enhanced production of cathelicidin
and CD14, and potentiation of host
defenses against M. tuberculosis and
other bacteria, fungi, and viruses.
25(OH)D
1,25 (OH)2D3
CD14 has been shown to be expressed in monocytes, macrophages, polymorphonuclear neutrophils

34. Randomized trial of vitamin D supplementation to
prevent seasonal influenza A in schoolchildren.
Urashima M, Am J Clin Nutr 2010;91:1255–1260.
Vitamin D(3)
supplements (1200 IU/d)
(n= 167) with placebo
(n= 167) in schoolchildren
From December 2008
through March 2009
incidence of influenza A,
diagnosed with influenza
antigen testing with a
nasopharyngeal swab
specimen.
RR for asthma attacks
1.0 –
0.5 –
0
0.17
P=0.006
in asthmatic children who had
been vitamin D supplemented

35. Low serum 25-hydroxyvitamin D levels are associated with
increased risk of viral coinfections in wheezing children
Jartti JACI 2010;126:1074
284 hospitalized
wheezing children
(median age 1.6 years).
Nasopharyngeal
aspirate samples
for 18 different
viruses.
Serum 25(OH)D
measurements.
0.91
For any 10 nmol/L (4 ng/mL)
increase in vitamin D serum
levels OR for
1.0 –
0.5 –
0
0.92
RSV rhinovirus
0.91
multiple
viral cause
Induced wheezingTo convert 25-OH vitamin D concentrations from
nanomoles per liter to ng/mL, divide by 2.496.

36. Associations of cord-blood 25(OH)D levels
with probabilities of cumulative wheeze or
incident asthma by 5 years of age
Cord-Blood 25-Hydroxyvitamin D Levels and Risk of
Respiratory Infection, Wheezing, and Asthma
Camargo Pediatrics 2011;127:180
 25(OH)D in cord blood
from 922 newborns.
 History of respiratory
infection at 3 mo of age
or a history of wheezing
at 15 mo and then
annually thereafter.
 Doctor-diagnosed
asthma by age 5 years.
To convert 25-OH vitamin D concentrations from
nanomoles per liter to ng/mL, divide by 2.496.

37. Associations of cord-blood 25(OH)D levels
with probabilities of cumulative wheeze or
incident asthma by 5 years of age
Cord-Blood 25-Hydroxyvitamin D Levels and Risk of
Respiratory Infection, Wheezing, and Asthma
Camargo Pediatrics 2011;127:180
 25(OH)D in cord blood
from 922 newborns.
 History of respiratory
infection at 3 mo of age
or a history of wheezing
at 15 mo and then
annually thereafter.
 Doctor-diagnosed
asthma by age 5 years.
To convert 25-OH vitamin D concentrations from
nanomoles per liter to ng/mL, divide by 2.496.
Cord blood
25(OH)D levels were
inversely
associated with
wheeze throughout
early childhood but
had no association
with incident asthma.

38. HOW COULD VITAMIN D PROTECT
AGAINST ASTHMA MORBIDITY?
Enhanced Steroid Responsiveness
The overall mechanism of steroid hormone
action is the regulation of gene expression. The
lipophilic steroid hormones are carried into the
blood stream with the majority of hormone
reversibly bound to carrier proteins and a small
amount of free steroids. The free steroid
diffuses throught the cell membrane and enters
cells. The sensitive cells contain a high affinity
steroid hormone receptor either in the cytosol
or in the nucleus. The steroid receptor complex
enters the nucleus and initiates a
conformational change that involves
dimerization to activate the complex to interact
with specific regions on cellular DNA referred
to as hormone responsive elements (HRE). This
initiates the process of transcription to produce
mRNA and translations to produce proteins.
These proteins regulate cell function, growth
differentiation, etc TGF-β and IL-10

39. Reversing the defective induction of IL-10–secreting
regulatory T cells in glucocorticoid-resistant asthma
patients. Xystrakis E, J Clin Invest 2006;116:146–155.
adding vitamin D to cell cultures increases
glucocorticoid-induced secretion of
IL-10 by Tregs
Patients with severe
asthma failling to
demonstrate clinical
improvement upon
glucocorticoid therapy
(steroid resistant = SR)
Dexamethasone does
not enhance secretion of
IL-10 by their CD4+ T
cells

40. 54 adult asthmatics
 serum 25(OH)D,
lung function,
AHR
GC response as
measured by
dexamethasone induced
expression of MAP
kinase phosphatase-1
(MKP-1) by PBMCs, a
negative regulator of MAPK
signal transduction pathways
for pro-inflammatory genes
Serum vitamin D vs DEX-induced
MKP-1 expression on PBMC
r = 0.4 p = 0.04
Vitamin D Levels, Lung Function and Steroid Response
in Adult Asthma. Sutherland ER, AJRCCM. 2010;181:669

41. 54 adult asthmatics
 serum 25(OH)D,
lung function,
AHR
GC response as
measured by
dexamethasone induced
expression of MAP
kinase phosphatase-1
(MKP-1) by PBMCs.
Serum vitamin D vs baseline TNF-α
r = -0.3 p = 0.01
Vitamin D Levels, Lung Function and Steroid Response
in Adult Asthma. Sutherland ER, AJRCCM. 2010;181:669
Higher serum
vitamin D
concentrations were
associated with
decreased baseline
expression of
TNF-a
by PBMCs

42. Decreased serum vitamin D levels in children with
asthma are associated with increased corticosteroid use
Searing JACI 2010;125:995
 25-hydroxyvitamin D
serum levels.
 100 asthmatic children.
 VitD's effects on
dexamethasone (DEX)
induction of mitogen-
activated protein kinase
phosphatase 1 and IL-10
in PBMCs.
29
40 –
30 –
20 –
10 –
0
Vitamin D serum levels ng/mL
(median)
35
ICS (-)ICS (+)
p=0.0475

43. Decreased serum vitamin D levels in children with
asthma are associated with increased corticosteroid use
Searing JACI 2010;125:995
 25-hydroxyvitamin D
serum levels.
 100 asthmatic children.
 VitD's effects on
dexamethasone (DEX)
induction of mitogen-
activated protein kinase
phosphatase 1 and IL-10
in PBMCs.
25
40 –
30 –
20 –
10 –
0
Vitamin D serum levels ng/mL
(median)
32
(-)(+)
Oral corticosteroids
p=0.02

44. HOW COULD VITAMIN D PROTECT
AGAINST ASTHMA MORBIDITY?
Down-regulation of atopy

45. ABPA (-)
Vitamin D3 attenuates Th2 responses to Aspergillus
fumigatus mounted by CD4+ T cells from cystic fibrosis
patients with allergic bronchopulmonary aspergillosis.
Kreindler JL, J Clin Invest 2010;120:3242-54.
ABPA (+)
patients
Vitamin D serum level (ng/mL)
36.56
p=0.02
40 –
30 –
20 –
10 –
0
22.04
cohorts of A. fumigatus-
colonized CF patients
 with and without
Allergic Bronchopulmonary
Aspergillosis (ABPA) Aspergillus
sIgE

46. Vitamin D and atopy and asthma phenotypes in
children: a longitudinal cohort study.
Hollams EM, Eur Respir J. 2011;38:1320-27
1. Serum vitamin D levels in children
at both ages were negatively
associated with concurrent
allergic phenotypes;
2. Gender stratification revealed
that this association was
restricted mainly to boys.
3. Further, vitamin D levels at age 6
were significant predictors of
subsequent atopy/asthma-
associated phenotypes at age 14.
an unselected community
birth cohort in Australia
6-year-olds (n=989) and
14-year-olds (n=1380);
associations between
vitamin D status and
biological signatures
indicative of allergy and
asthma development in
children aged 6 and 14 years

47. Probability of atopic sensitisation decreases
as vitamin D increases in males only
Vitamin D and atopy and asthma phenotypes in
children: a longitudinal cohort study.
Hollams EM, Eur Respir J. 2011;38:1320-27
an unselected community
birth cohort in Australia
6-year-olds (n=989) and
14-year-olds (n=1380);
associations between
vitamin D status and
biological signatures
indicative of allergy and
asthma development in
children aged 6 and 14 years

48. an unselected community
birth cohort in Australia
6-year-olds (n=989) and
14-year-olds (n=1380);
associations between
vitamin D status and
biological signatures
indicative of allergy and
asthma development in
children aged 6 and 14 years
Mean vitamin D levels and mean HDM-IgE
titers combined over the three year period
Vitamin D and atopy and asthma phenotypes in
children: a longitudinal cohort study.
Hollams EM, Eur Respir J. 2011;38:1320-27

49. Variation in the average immunoglobulin E by
25-hydroxyvitamin D concentration in
the 1958 British cohort at the age of 45 years.
Serum 25-hydroxyvitamin D and IgE a significant but
nonlinear relationship Hyppönen Allergy 2009;64:613
9377 participants
in the 1958
British birth
cohort.
Assessment at
45 years of age.
<10 ng/mL >50 ng/mL

50. Variation in the average immunoglobulin E by
25-hydroxyvitamin D concentration in
the 1958 British cohort at the age of 45 years.
Serum 25-hydroxyvitamin D and IgE a significant but
nonlinear relationship Hyppönen Allergy 2009;64:613
9377 participants
in the 1958
British birth
cohort.
Assessment at
45 years of age.
There may be a
threshold effect
with both low
and high
25(OH)D levels
associated with
elevated IgE
concentrations.
>50 ng/mL<10 ng/mL

51. Cord blood 25-hydroxyvitamin D levels are associated
with aeroallergen sensitization in children from Tucson,
Arizona. Rothers J, JACI 2011;128:1093-1099.
Cord blood 25(OH)D levels
measured in 219 participants in
the Tucson Infant Immune
Study,
total IgE and specific IgE
levels to 6 aeroallergens were
measured at 1, 2, 3, and 5 years.
SPTs and physician-diagnosed
active allergic rhinitis and
asthma at age 5 years.
OR for detectable inhalant
allergen-specific IgE
1
2
4
2.4
P=0.03
P=0.01

52. It is possible that in the presence of vitamin D, Treg cells
develop and function normally in suppressing inappropriate TH1 and
TH2 responses to environmental exposure (ie, allergens, lack of
infections, and so forth), leading to a more balanced immune
response.
On the other hand, if vitamin D is lacking, Treg cells may not
develop and function normally, and in the presence of the
appropriate environmental influence, TH1 or TH2 responses are
allowed to proceed unabated, leading to disease.
The paradox of vitamin D effects

53. HOW COULD VITAMIN D PROTECT
AGAINST ASTHMA MORBIDITY?
Other potential mechanisms: obesity

54. Season of birth and prevalence of overweight and
obesity in Canada. Wattie N, Early Hum Dev 2008;84:539-47.
Canadian Community
Health Survey,
birth data of respondents
12 to 64 years old
among the 20-64 year olds, those
in the obese III (BMI≥40 kg/m2)
category OR for
2 –
1 –
0
1.54
being born in the winter

55. Vitamin D deficiency and anthropometric indicators of
adiposity in school-age children: a prospective study.
Gilbert-Diamond D, Am J Clin Nutr 2010;92:1446-51.
vitamin D serostatus and
changes in body mass index
(BMI; in kg/m²), skinfold-
thickness ratio
(subscapular-to-triceps),
waist circumference, and
height
a longitudinal study in
children from Bogota,
Colombia.
Follow-up: 30 months
Vitamin D-deficient children vs
vitamin D-sufficient children had:
1) an adjusted 0.1/y greater
change in BMI
(P for trend = 0.05).
2) a 0.03/y greater change in
subscapular-to-triceps skinfold-
thickness ratio and
3) a 0.8 cm/y greater change in
waist circumference

56. HOW COULD VITAMIN D PROTECT
AGAINST ASTHMA MORBIDITY?
Other potential mechanisms: obesity
Given that overweight or obesity has been associated with
asthma and increased asthma severity in children and
adults, it is reasonable but highly speculative to postulate
that vitamin D supplementation reduces asthma morbidity
through beneficial effects on weight control.
An official American Thoracic Society Workshop report:
obesity and asthma.
Dixon AE, Proc Am Thorac Soc 2010;7:325-35.

57. HOW COULD VITAMIN D PROTECT
AGAINST ASTHMA MORBIDITY?
Other potential mechanisms: lung function

58. Relationship between serum 25-hydroxyvitamin D and
pulmonary function in the Third National Health and
Nutrition Examination Survey.
Black PN, Chest 2005;128:3792–3798.
a cross-sectional
survey of 14,091
people > 20 years of
age,
spirometry, and
serum 25-hydroxy
vitamin D levels
Mean increase for the highest quintile of serum
25-hydroxy vitamin D level
(>85.7 nmol/L – 34 ng/mL) compared with the
lowest quintile (<40.4 nmol/L - 16 ng/mL).
200 –
150 –
100 –
50 –
0
+
172mL
FVC FEV1
+
126mLp<0.0001
p<0.0001

59. HOW COULD VITAMIN D PROTECT
AGAINST ASTHMA MORBIDITY?
Other potential mechanisms:
regulating expression of
disease-susceptibility genes.

60. Vitamin D may influence asthma by regulating
expression of disease-susceptibility genes.
and some are in auto-immune pathways
in vitro binding of VDR in ~2,500 to 3,500
genes in Lymphoblastoid cell lines;
a fraction (~200-1,000) of these genes are
differentially expressed after calcitriol stimulation
•Ramagopalan SV, Genome Res 2010;20:1352-60. 97.
•Pike JW, J Steroid Biochem Mol Biol 2010;121:130-5.
•Hunninghake GM, BMC Pulm Med 2011;11:17.
•Li X, J Allergy Clin Immunol 2011;127:1457-65.
•Liu YJ. J Allergy Clin Immunol 2007;120:238-44;

61. Genome-wide association study reveals class I
MCH-restricted T cell-associated molecule gene (CRTAM)
variants interact with vitamin D levels to affect asthma
exacerbations. Du JACI 2012;129:368
Background
It has recently been shown that vitamin D deficiency
can increase asthma development and severity and that
variations in vitamin D receptor genes are associated
with asthma susceptibility.
Objective
We sought to find genetic factors that might interact
with vitamin D levels to affect the risk of asthma exacerbation.

62. Genome-wide association study reveals class I
MCH-restricted T cell-associated molecule gene (CRTAM)
variants interact with vitamin D levels to affect asthma
exacerbations. Du JACI 2012;129:368
• Genome-wide study
of gene–vitamin D
interaction on
asthma exacerbations.
• Population-based
and family-based
approaches.
• 23 polymorphisms.
We identified
3 common variants
class I MHC– restricted
T cell–associated molecule
gene (CRTAM)
that were associated with
an increased rate of
asthma exacerbations
based on the presence of
low circulating
vitamin D level.

63. Genome-wide association study reveals class I
MCH-restricted T cell-associated molecule gene (CRTAM)
variants interact with vitamin D levels to affect asthma
exacerbations. Du JACI 2012;129:368
• Genome-wide study
of gene–vitamin D
interaction on
asthma exacerbations.
• Population-based
and family-based
approaches.
• 23 polymorphisms.
We identified
3 common variants
class I MHC– restricted
T cell–associated molecule
gene (CRTAM)
that were associated with
an increased rate of
asthma exacerbations
based on the presence of
low circulating
vitamin D level.
These results were
replicated in a second
independent population.
CRTAM is highly expressed
in activated human CD81
and natural killer T cells,
both implicated in
asthmatic patients.

64. Vitamin D and Asthma
 Vitamin D
deficiency-insufficiency
 Onset of Disease
 Morbidity & Exacerbations
 Protective Mechanisms
 Summary & Conclusions
University of
Verona, Italy
Attilio Boner
attilio.boner@univr.it

65. Vitamin D serum concentration
modified from G Paul AJRCCM 2011
Lung maturity
& development
Viral
infections
Steroid
resposiveness Atopy
Asthma morbidity
Lung
Function
exacerbations Healthcare
utilization
?

66. Summary & Conclusions
Intervention trials are needed to assess the role of
vitamin D supplementation during pregnancy and early in
life to prevent asthma initiation.
Findings from several studies suggest beneficial effects
of vitamin D on asthma morbidity in relation to prevention
of viral infections, enhanced steroid responsiveness,
improved lung function.
There is currently weak and inconsistent evidence for a
link between vitamin D and atopic responses.

67.  Preliminary intervention studies, suggest an effect of
vitamin D on ameliorating ongoing disease but further
studies are needed in different groups such as infants,
children, adults, and ethnic minorities.
At this time, vitamin D supplementation is recommended
for patients who have a serum vitamin D (25[OH]D) level
<20 ng/ml, as this could potentially compromise asthma
but for sure will impair their musculoskeletal health and
may favor the onset of autoimmune diseases.
Summary & Conclusions

68. Vitamin D deficiency was the cause
Courtesy of Holick MF

69. ACKNOWLEDGMENTS
•Iolanda Chinellato MD
•Michele Piazza PhD
•Giuseppe Gallo student