The document discusses the multifaceted roles of vitamin D beyond skeletal health, including its influence on the immune system and associations with conditions such as atopic dermatitis and asthma. It highlights various studies on vitamin D supplementation during pregnancy and childhood, noting variable impacts on health outcomes. The importance of vitamin D levels in managing chronic conditions and the need for further research in this area are emphasized.

1. Vitamina D e ….
Le azioni extrascheletriche
Diego Peroni
U.O. Pediatria
Università di Pisa
 Le basi immunologiche
 L’associazione
 La supplementazione
 I problemi aperti
 Le conclusioni
diego.peroni@unipi.it

2. 1634: prima comparsa del termine “rickets”

3. The vitamin D receptor (VDR), the nuclear hormone
receptor that mediates most if not all of the functions
of its preferred ligand 1,25 dihydroxyvitamin D
[1,25(OH)2D] or calcitriol, is found in most tissuesis found in most tissues
of the body.of the body.
Indeed, many of these tissues also contain the enzyme, CYP27B1,enzyme, CYP27B1,
which converts the major circulating metabolite of vitamin D,
25 hydroxyvitamin D25 hydroxyvitamin D (25OHD calcidiolcalcidiol) , toto 1,25(OH)2D (calcitriol)1,25(OH)2D (calcitriol).
Thus, it has been suspected for some time that vitamin D exertsvitamin D exerts
its actions not only on classic tissues regulating calciumits actions not only on classic tissues regulating calcium
homeostasishomeostasis such as bonebone, gutgut and kidneykidney but also on other tissuesother tissues.
Multiple Functions of Vitamin D

4. Overview of vitamin D and its interactions with cells of
the immune system. Muehleisen B, JACI 2013;131:324-9.

5. Vitamin D and
immune system.
1α,25(OH)2D appears to
influence susceptibility
to and severity of
infection via multiple
mechanisms via the
innate and adaptive
immune system.
Gröber U,Gröber U,
Dermatoendocrinol.Dermatoendocrinol.
2013;5:331-472013;5:331-47

6. Vitamina D e ….
Le azioni extrascheletriche
Diego Peroni
U.O. Pediatria
Università di Pisa
 Le basi immunologiche
 L’associazione
 La supplementazione
 I problemi aperti
 Le conclusioni
diego.peroni@unipi.it

7. Vitamin D, the Gut Microbiome, and the Hygiene Hypothesis. How
Does Asthma Begin? S Weiss, AJCCM, 2015; 191:492
Interactions of vitamin D with the gut microbiome and the fetal
immune system. Vitamin D up-regulates TGF-beta1 and IL-10, which
will enhance Treg function and down-regulate CD4 T cells, reducing
both Th1 and Th2 CD41 cell inflammation.

8. Vitamin D, the Gut Microbiome, and the Hygiene Hypothesis. How
Does Asthma Begin? S Weiss, AJCCM, 2015; 191:492
Vitamin D also enhances antigenic traffic between dendritic cells
and Tregs. The gut microbiome is the primary source of antigen for
Treg cell processing and may also influence the development of
immunity in the fetus. Vitamin D controls the development of GALT
and dendritic cell trafficking from the gut dendritic cells in the gut
epithelium to the Tregs.

9. Studi che hanno valutato l’associazione tra
dermatite atopica e vitamina D

10. Correlation between serum 25-hydroxyvitamin D levels
and severity of atopic dermatitis in children.
Peroni DG, Br J Dermatol. 2011;164:1078-82.
Correlation between serum vitamin D
levels and individual SCORAD values.
37 children (8 months and
12 years) with AD,
SCORAD index,
Serum levels of
25-hydroxyvitamin D
sIgE to S. aureus
and to M. furfur

11. Serum Vitamin D levels and Vitamin D supplementation
do not correlate with the severity of chronic eczema in
children. Galli E, Eur Ann Allergy Clin Immunol. 2015;47(2):41-7.
89 children with chronic
eczema divided into two
groups according to the
state of sensitization
(YES/NO).
a daily oral Vitamin D3
supplementation
(2000 IUs)
for 3 months or
no supplementation.
1) Vitamin D concentrations in patients with
moderate and severe eczemamoderate and severe eczema were not
statistically different from Vitamin D
concentration detected in the serum of
patients with mild eczemamild eczema.
2)2) No correlationNo correlation was found between
Vitamin D levels, total IgEstotal IgEs and
SCORADSCORAD index, both in the Sensitized
and in the Not-Sensitized group.
3) Vitamin D3 supplementation did notsupplementation did not
influence the SCORAD severity or theinfluence the SCORAD severity or the
total IgEs concentration.total IgEs concentration.

12. Altri studi che hanno valutato l’associazione tra
dermatite atopica e vitamina D

13. Cord serum 25-hydroxyvitamin D and risk of early childhood
transient wheezing and atopic dermatitis.
Baiz N, JACI; 2014; 133:147
aim was to
investigate in
239 newborns the
associations
between cord
serum 25(OH)D
levels and
asthma,wheezing,
allergic rhinitis,
and atopic
dermatitis in the
offspring from
birth to 5 years.
Adjusted associations between cord serum 25(OH)D
levels and predicted probabilities of atopic dermatitis by
age of 5 years

14.  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 significantlyVitamin D levels were significantly
and inversely associated with: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

15. 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

16. Vitamina D e ….
Le azioni extrascheletriche
Diego Peroni
U.O. Pediatria
Università di Pisa
 Le basi immunologiche
 L’associazione
 La supplementazione
nella prevenzione
 I problemi aperti
 Le conclusioni
diego.peroni@unipi.it

17. Predictors of vitamin D status in subjects that consume a
vitamin D supplement. Levy M., Eur. J. Clin. Nutr. 2015; 69, 84
Retrospective,
cross-sectional
study involving 743
volunteers.
Serum 25-hydroxy-
vitamin D
(25(OH)D) level and
the variables diet,
supplement usage,
latitude of
residence, ethnicity,
age and body mass
index (BMI)
winter summer

18. Predictors of vitamin D status in subjects that consume a
vitamin D supplement. Levy M., Eur. J. Clin. Nutr. 2015; 69, 84
Supplemental vitamin D3 consumption was the most
significant positive predictor, whereas BMI was
the most significant negative predictor. Negative
predictors were: African American, Asian and
Hispanic race in the summer; latitude of residence
<36 °N, Asian and Hispanic ethnicity in the winter

19. Maternal nutrition during pregnancy and risk of asthma, wheeze,
and atopic diseases during childhood: a systematic review and
meta-analysis. Beckhaus A, Allergy 2015; 70: 1588
Pooled difference for maternal dietary vitamin D
intake during pregnancy and childhood wheeze.
Current evidence suggests a protective effect of maternal intake of each of three
vitamins or nutrients (vitamin D, vitamin E, and zinc) against childhood wheeze but is
inconclusive for an effect on asthma or other atopic conditions.

20. Vitamin D During Pregnancy and Infancy and Infant Serum 25-
Hydroxyvitamin D Concentration. C Grant, Pediatrics 2014;133:e143
Pregnant mothers,
from 27 weeks’
gestation to birth,
and then their
infants, from birth
to age 6 months,
were randomly
assigned to 1 of 3
mother/infant
groups:
placebo/placebo,
vitamin
D3 1000/400 IU, or
vitamin D3
2000/800 IU

21. Reduced primary care respiratory infection visits following
pregnancy and infancy vitamin D supplementation: a randomised
controlled trial. Grant, Acta Paediatrica, 2015; 104:396.
Pregnant mothers,
from 27 weeks’
gestation to birth,
and then their
infants, from birth
to age 6 months,
were randomly
assigned to 1 of 3
mother/infant
groups:
placebo/placebo,
vitamin
D3 1000/400 IU,
or vitamin D3
2000/800 IU
Time (in days) to first primary care visit for an acute
respiratory infection for children randomised to placebo,
lower-dose vitamin D3 or higher dose vitamin D3.

22. Vitamin D supplementation during pregnancy and infancy reduces
aeroallergen sensitization: a randomized controlled trial.
Grant, Allergy 2016
Woman/infant pairs were randomized to: placebo/placebo, 1000
IU/400 IU or 2000 IU/800 IU. When the children were 18 months
old, we measured sIgE and identified acute primary care visits

23. Vitamin D supplementation during pregnancy and infancy reduces
aeroallergen sensitization: a randomized controlled trial.
Grant, Allergy 2016
Woman/infant pairs were randomized to: placebo/placebo, 1000
IU/400 IU or 2000 IU/800 IU. When the children were 18 months
old, we measured sIgE and identified acute primary care visits
Vitamin D supplementation during pregnancy and infancy
reduces the proportion of children sensitized to mites at
age 18 months. Preliminary data indicate a possible
effect on primary care visits where asthma is diagnosed.

24. Effect of Vitamin D3 Supplementation During Pregnancy on Risk of
Persistent Wheeze in the Offspring. Chawes, JAMA. 2016;315(4):353.
COPSAC study cohort.
Vitamin D3 (2400 IU/d; n=315) or matching placebo tablets (n=308) from
pregnancy week 24 to 1 week postpartum.
All women received 400 IU/d of vitamin D3 as part of usual pregnancy care.
Age at onset of persistent wheeze in the first 3 years of life

25. Effect of Vitamin D3 Supplementation During Pregnancy on Risk of
Persistent Wheeze in the Offspring. Chawes, JAMA. 2016;315(4):353.
Effect of Vitamin D3 Supplementation
on Risk of Persistent Wheeze in
Children in the COPSACThe use of 2800 IU/d of
vitamin D3 during the third
trimester of pregnancy
compared with 400 IU/d did
not result in a statistically
significant reduced risk
of persistent wheeze in the
offspring through age 3 years.
However, interpretation of the
study is limited by a wide CI
that includes a clinically
important protective effect.

26. Effect of Prenatal Supplementation With Vitamin D on Asthma or
Recurrent Wheezing in Offspring by Age 3 Years.
Litonjua, JAMA. 2016;315(4):362
The Vitamin D Antenatal Asthma Reduction Trial 440 women were randomized to
receive daily 4000 IU vitamin D plus 400 IU, and 436 women were randomized to
receive a placebo plus a prenatal vitamin containing 400 IU vitamin D.
Coprimary outcomes of (1) parental report of physician-diagnosed asthma or
recurrent wheezing through 3 years of age and (2) third trimester maternal 25-
hydroxyvitamin D levels.

27. Effect of Prenatal Supplementation With Vitamin D on Asthma or
Recurrent Wheezing in Offspring by Age 3 Years.
Litonjua, JAMA. 2016;315(4):362
The Vitamin D Antenatal Asthma Reduction Trial 440 women were randomized to
receive daily 4000 IU vitamin D plus 400 IU, and 436 women were randomized to
receive a placebo plus a prenatal vitamin containing 400 IU vitamin D.
Coprimary outcomes of (1) parental report of physician-diagnosed asthma or
recurrent wheezing through 3 years of age and (2) third trimester maternal 25-
hydroxyvitamin D levels.
In pregnant women at risk of having a child with
asthma, supplementation with 4400 IU/d of vitamin D
compared with 400 IU/d significantly increased vitamin
D levels in the women. The incidence of asthma and
recurrent wheezing in their children at age 3 years was
lower by 6.1%, but this did not meet statistical
significance

28. Vitamina D e ….
Le azioni extrascheletriche
Diego Peroni
U.O. Pediatria
Università di Pisa
 Le basi immunologiche
 L’associazione
 La supplementazione
nella terapia
 I problemi aperti
 Le conclusioni
diego.peroni@unipi.it

29. Effectiveness of vitamin D supplementation in the management
of atopic dermatitis: a review of current evidence.
Demirjian M. Curr Nutr Food Sci 2014; 10: 12

30. Vitamin D supplementation in the treatment of atopic dermatitis: a
clinical trial study.
Amestejani M, J Drugs Dermatol. 2012;11(3):327-30
60 AD patients
(mean age 23 yrs)
living in Tehran, Iran
Group D, 1600 IU1600 IU
cholecalciferolcholecalciferol
(vitamin D n= 30) and second
group placebo (n= 30)
for 2 monthsfor 2 months
severity of AD based on
SCORAD
(Scoring Atopic Dermatitis)
and TIS
(Three Item Severity score)
For both the SCORAD index and
TIS value, the vitamin Dthe vitamin D
supplemented group showedsupplemented group showed
improvement in patients with mild,improvement in patients with mild,
moderate, and severe AD.moderate, and severe AD.
All of these measures were statistically
significant except for the TIS value in the
moderate category of patients.
A statistically significant improvement was
not seen for patients taking the placebo pill
in any of the severity categories.

31. Studi più recenti di supplementazione

32. Randomized trial of vitamin D supplementation for
winter-related atopic dermatitis in children.
Camargo CA Jr, J Allergy Clin Immunol. 2014;134(4):831-835.
average % change from
the baseline EASI score
-00
-10 –
-20 –
-30 –
-16%
-29%
p=0.02
Vitamin D
Placebo
104 Mongolian
children with
winter-related AD
(age 2-17 yrs)
AD score 10 to 72 using
the Eczema Area andEczema Area and
Severity Index (EASI)Severity Index (EASI)
oral cholecalciferoloral cholecalciferol
(1000 IU/day)(1000 IU/day) versus
placebo for 1 monthfor 1 month.

33. Studi più recenti di supplementazione
Nei bambini con dermatite atopica severa e livelli
ridotti di 25(OH)D potrebbe essere indicato un
breve trial con vitamina D, per ripristinare uno
stato vitaminico D sufficiente e valutare
l’eventuale effetto di modulazione della severità
della dermatite atopica. Resta la necessità di
ulteriori studi…

34. Effect of Vitamin D and Inhaled Corticosteroid
Treatment on Lung Function in Children
Chen Wu A., AJRCCM 2012; 186: 508–513
Change in prebronchodilator FEVChange in prebronchodilator FEV11
Change in prebronchodilatorChange in prebronchodilator
FEVFEV11 % predicted% predicted
P = 0.0072
vitamin D sufficiencyvitamin D sufficiency (>30 ng/ml), insufficiencyinsufficiency (20–30 ng/ml),
deficiencydeficiency (<20 ng/ml)

35. Vitamin D supplementation in children may prevent
asthma exacerbation triggered by acute respiratory
infection. Majak P, J Allergy Clin Immunol 2011;127:1294
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

36. Improved control of childhood asthma with low-dose, short-term
vitamin D supplementation: a randomized, double-blind, placebo-
controlled trial. Tachimoto, Allergy 2016.
placebo-controlled trial
comparing vitamin D3
supplements (800
IU/day) with placebo
for 2 months in
schoolchildren with
asthma. The primary
outcomes were
frequency and severity
by GINA.
Schoolchildren
received vitamin D
(n = 54) or placebo
(n = 35).
Low-dose, short-term vitamin D
supplementation in addition to
standard treatment may improve levels of
asthma control in schoolchildren.

38. Vitamina D e ….
Le azioni extrascheletriche
Diego Peroni
U.O. Pediatria
Università di Pisa
 Le basi immunologiche
 L’associazione
 La supplementazione
 I problemi aperti
 Le conclusioni
diego.peroni@unipi.it

39. The lower defined threshold value for bone healththreshold value for bone health
(25OHD ≥ 20 ng/mL(25OHD ≥ 20 ng/mL [50 nmol/L])[50 nmol/L]),
Holick MF, J Clin Endocrinol Metab 2011;96:1911–30
Rosen CJ, J Clin Endocrinol Metab 2012;97:1146–52.
Serum level of 25OHD 30–40 ng/mL30–40 ng/mL
(75–100 nmol/L)(75–100 nmol/L) has been suggested asas
a lower thresholda lower threshold of an optimal serum level
for the immune effectsfor the immune effects of vitamin D.
Vieth R, Am J Clin Nut 2007;85:649–50.
Bischoff-Ferrari HA, Am J Clin Nut 2006; 84:18–28.
MoreMore than one-third of the population worldwideone-third of the population worldwide may have levels of
vitamin D < 20 ng/mL< 20 ng/mL (50 nmol/L)(50 nmol/L). Hilger J. British J Nut 2014;111:23–45.
Vitamin D levels optimal for overall health.

40. Vitamin D–Binding Protein Modifies the Vitamin D–Bone Mineral
Density Relationship. Powe, JBMR; 2011: 26, 1609.
The free hormone hypothesis postulates that only hormones
liberated from binding proteins enter cells and produce biologic
action.
25(OH)D and 1,25-dihydroxyvitamin D3 [1,25(OH)2D3] circulate
bound to vitamin D–binding protein (85% to 90%) and albumin (10%to
15%), with less than 1% of circulating hormone in its free form.
In mice, vitamin D–binding protein (DBP) prolongs the serum half-life
of 25(OH)D and protects against vitamin D deficiency by serving as a
vitamin D reservoir. However, DBP also limits the biologic activity of
injected 1,25(OH)2D3 in mice and inhibits the action of vitamin D on
monocytes and keratinocytes in vitro.
The significance of circulating DBP levels with regard to vitamin D’s
biologic action in humans is unclear.

41. Vitamin D and DBP: The free hormone hypothesis
revisited. Chun, J Steroid Biochem Mol Biol. 2014; 144: 132

42. Vitamin D–Binding Protein and Vitamin D Status of Black Americans
and White Americans. Powe, NEJM 2013; 369: 1991.
(2085 participants)
measured levels of total
25-hydroxyvitamin D,
vitamin D–binding
protein, and parathyroid
hormone as well as bone
mineral density (BMD).
We genotyped study
participants for two
common polymorphisms

43. Vitamin D–Binding Protein and Vitamin D Status of Black Americans
and White Americans. Powe, NEJM 2013; 369: 1991.
(2085 participants)
measured levels of total
25-hydroxyvitamin D,
vitamin D–binding
protein, and parathyroid
hormone as well as bone
mineral density (BMD).
We genotyped study
participants for two
common polymorphisms

44. Vitamin D–Binding Protein and Vitamin D Status of Black Americans
and White Americans. Powe, NEJM 2013; 369: 1991.
(2085 participants)
measured levels of total
25-hydroxyvitamin D,
vitamin D–binding
protein, and parathyroid
hormone as well as bone
mineral density (BMD).
We genotyped study
participants for two
common polymorphisms
Community-dwelling black Americans, as compared with
whites, had low levels of total 25-hydroxyvitamin D and
vitamin D–binding protein, resulting in similar
concentrations
of estimated bioavailable 25-hydroxyvitamin D. Racial
differences in the prevalence of common
genetic polymorphisms provide a likely explanation for
this observation

45. Response of vitamin D binding protein and free vitamin D
concentrations to vitamin D supplementation in hospitalized
premature infants. Hanson, J Ped End Metab 2015; 28: 1107
32 infants < 32 wks’
gestation were
randomized to two
different levels of
vitamin D3
supplementation
(400 vs. 800
IU/day).
25(OH)D levels were
measured by LC-
MS/MS; DBP was
measured by
validated ELISA.
Free vitamin D was
calculated using
molar ratios of
25(OH)D and DBP

46. Response of vitamin D binding protein and free vitamin D
concentrations to vitamin D supplementation in hospitalized
premature infants. Hanson, J Ped End Metab 2015; 28: 1107
32 infants < 32 wks’
gestation were
randomized to two
different levels of
vitamin D3
supplementation
(400 vs. 800
IU/day).
25(OH)D levels were
measured by LC-
MS/MS; DBP was
measured by
validated ELISA.
Free vitamin D was
calculated using
molar ratios of
25(OH)D and DBP
Vitamin D binding protein acts as a reservoir for 25(OH)
D, controlling the bioavailability to target organs.
Supplementation with vitamin D3 increased the free
portion
of the vitamin D metabolite, calculated from measured
DBP levels, providing increased bioavailable substrate.

47. Vitamina D e ….
Le azioni extrascheletriche
Diego Peroni
U.O. Pediatria
Università di Pisa
 Le basi immunologiche
 L’associazione
 La supplementazione
 I problemi aperti
 Le conclusioni
diego.peroni@unipi.it

48. Based on the results reported in the trials by Chawes et al and
Litonjua et al, what should clinicians do?
Given the lack of any major unwanted effects observed in either of these trials,
prescribing a higher than recommended vitamin D–containing supplement
during pregnancy to mothers who are at high risk of having children with
asthma (ie, with a history of asthma, eczema,or allergic rhinitis) seems to be a
reasonable strategy, especially if the pregnant woman has evidence of vitamin D
deficiency.
However, the data in these 2 RCTs do not support the use of very high-dose
vitamin D
These studies provide support for a larger adequately powered study of the role
of vitamin D supplementation during pregnancy for asthma prevention that
includes plans for rigorous outcome assessment and long-term follow-up.
Then it may be possible to know whether maternal vitamin D supplementation
can reduce the risk of childhood asthma.
Inconclusive Results of Randomized Trials of Prenatal Vitamin D
for Asthma Prevention in Offspring.
Curbing the Enthusiasm. E. von Mutius, F Martinez; JAMA 2016

49. Because different functions of vitamin D
(eg, bone mineral metabolism and
immunologic,) appear in different
serum levels and are dose dependent and there arethere are
suggestions that levelssuggestions that levels
greater than 40-50 ng/mL are optimal for vitamin Dgreater than 40-50 ng/mL are optimal for vitamin D
immune functions.immune functions.
•Brehm JM, Serum vitamin D levels and severe asthma exacerbations in the Childhood Asthma
Management Program study. J Allergy Clin Immunol. 2010;126:52e58.
•Hollis BW, Circulating vitamin D (3) and 25 hydroxyvitamin D in humans: an important tool to
define adequate nutritional vitamin D status. J Steroid Biochem Mol Biol. 2007;103:631e634.
•Taback SP, Simons FE. Anaphylaxis and vitamin D: A role for the sunshine hormone?
J Allergy Clin Immunol. 2007;120:128e130.
Conclusions

50. Because different functions of vitamin D
(eg, bone mineral metabolism and
immunologic,) appear in different
serum levels and are dose dependent and there arethere are
suggestions that levelssuggestions that levels
greater than 40-50 ng/mL are optimal for vitamin Dgreater than 40-50 ng/mL are optimal for vitamin D
immune functions.immune functions.
Conclusions
David Barker
born 29 June 1938;
died 27 August 2013
DOHDDOHD
The prenatal and early life period have been
identified as windows ofwindows of
opportunity’opportunity’ during which
immune responses can be permanently
programmed and therefore interventional studies
are needed.

51. Le azioni extrascheletriche della vitamina D
Nelle infezioni, nella dermatite atopicaNelle infezioni, nella dermatite atopica
Nella prevenzione delle allergieNella prevenzione delle allergie