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COMPANY NAME
Vitamin D and AsthmaVitamin D and Asthma
Jaichat Mekaroonkamol MD.
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Outlines
Vitamin D metabolism and physiology
Potential pharmacological role of vitamin D
supplementation in the treatment of severe asthma
Associations of vitamin D with allergic disease
Epidemiology of vitamin D deficiency
Vitamin D and the immune systemLOGOLOGO
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Vitamin D metabolism and physiology
• Sources of vitamin D• Vitamin D metabolism• Definition of vitamin D
deficiency and insufficiency
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Sources of vitamin D
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Holick MF. Vitamin D deficiency. N Engl J Med 2007;357:266–81.
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Holick MF. Vitamin D deficiency. N Engl J Med 2007;357:266–81.
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Vitamin D metabolism
Holick MF. Vitamin D deficiency. N Engl J Med 2007;357:266–81.
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Effects of vitamin D on immune disorders with special regard to asthma, COPD and autoimmune diseases: a short review Expert Rev. Respir. Med. 6(6), 683–704 (2012)
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Definition
Serum 25[OH]D is the best indicatorThere are no consensus guidelines available on
optimal levels of serum 25[OH]D
Mayo Clin Proc 2006Am J Clin Nutr 2006N Engl J Med 2007
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Definition
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Who is at risk
A. Gupta et al. / Paediatric Respiratory Reviews 13 (2012) 236–243.
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Epidemiology of vitamin D deficiency
Vitamin D skin metabolism is influenced by melanin content of the skin Age factors affecting sun exposure (latitude, season,
time outdoors, and clothing) body fat sunscreen use
Dietary intake (mostly from oily fish, fortified grains, and dairy products) and supplements are a secondary source of vitamin D
Lange NE, Litonjua A, Hawrylowicz CM, Weiss S. Vitamin D, the immunesystem and asthma. Expert Rev Clin Immunol 2009;5:693–702.
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Vitamin D Status: United States, 2001–2006. CDC March 2011
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Vitamin D Status: United States, 2001–2006. CDC March 2011
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332 cases 98 cases of postmenopausal women 104 cases of previously cited urban elderly women 130 cases of rural elderly women
Calcidiol at ≤ 35 ng/ml (significant increase in PTH) which indicated the level of vitamin D deficiency
Srinagarind Med J 2006
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71513322311N =
vitamin D
>45>40-45>35-40>30-35>25-30<=25
mean
(95
%C
I) o
f P
TH
50
40
30
20
10
0
•Clinical vitamin D inadequacy is the level of calcidiol that cause significantly increase in
serum PTH
McKenna MJ Osteoporos Int 1998; Scharla SH Osteoporos Int 1998
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386104130102N =
Subgroup of population
premenurban elderlyrural elderlyearly postmen
mean
(95%
CI
calc
idio
l) (
ng/m
l)50
40
30
20
44.89 (1.9)
33.22(1.4)32.65 (1.74)
the calcidiol level among pre-menopausal women, early post-the calcidiol level among pre-menopausal women, early post-
menopausal women, urbanized elderly and rural elderly womenmenopausal women, urbanized elderly and rural elderly women
35 ng/ml
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0
10
20
30
40
50
60
70
80
prevalence of vitamin D inadequacy (%)
Pre-men women
Early post-men
Urbanized elderly
Rural elderly
77.98%
60%65.4%
15.4%
Pre
-men
. wom
en
Ear
ly p
ost-
men
Urb
aniz
ed e
lder
ly
Rur
al e
lder
ly
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Subjects consisted of 2,641 adults aged 15 - 98 years randomly selected from the Thai 4th
National Health Examination Survey (2008-9)Serum 25 hydroxyvitamin D were measured by
liquid chromatography/tandem mass spectrometry
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Chailurkit et al. BMC Public Health 2011
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Chailurkit et al. BMC Public Health 2011
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Chailurkit et al. BMC Public Health 2011
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Vitamin D inadequate
45.2%
Vitamin D deficiency
5.7%
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COMPANY NAME
Roles of Vitamin D
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Calcium homeostasis
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Immunomodulator
J Allergy Clin Immunol 2013;131:324-9
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Immunomodulator
J Allergy Clin Immunol 2013;131:324-9
the final activation step for 25OH-D3 to 1,25(OH)2-D3 is quickly stimulated in monocytes and epithelial cells•Toll-like receptor (TLR) 2 ligands•TGF-b or IFN-g
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Immunomodulator
1.Increasing antimicrobial action Cathelicidin
2.Decrease inflammation
IL-10 secreting Treg
J Allergy Clin Immunol 2013;131:324-9
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Immunomodulator
J Allergy Clin Immunol 2013;131:324-9
Improve antimicrobial defenses• induces endogenous expression of the
antimicrobial peptide cathelicidin (skin, monocyte, lung)
• enhanced other elements of the skin innate immune system ex defensin
Increased values of the epidermallipid synthesis enzymes fatty acid synthase
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Immunomodulator
J Allergy Clin Immunol 2013;131:324-9
• Induces autophagy in human macrophages. • Autophagy is the ingestion of sequestered
material inside phagosomes• Important in the defense against infections,
such as in patients with tuberculosis
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Nature Clinical Practice Endocrinology & Metabolism, 2008
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Immunomodulator
J Allergy Clin Immunol 2013;131:324-9
• Vitamin D induces cathelicidin• cathelicidin was required for
cytotoxic activity of natural killer cells
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Immunomodulator
J Allergy Clin Immunol 2013;131:324-9
Decreased expression of TLRs and suppressed TLR-mediated
inflammation
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Immunomodulator
J Allergy Clin Immunol 2013;131:324-9
• Decreased immune receptor expression on dendritic cells (DCs)
• Inhibited DC activation by LPS
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Immunomodulator
J Allergy Clin Immunol 2013;131:324-9
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Immunomodulator
J Allergy Clin Immunol 2013;131:324-9
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Immunomodulator
J Allergy Clin Immunol 2013;131:324-9
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Immunomodulator
J Allergy Clin Immunol 2013;131:324-9
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Associations Associations of vitamin D of vitamin D with allergic with allergic
diseasedisease
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Vitamin D and Allergic disease
Promote immune tolerancePromoting development and increased activity of regulatory T cellRegulating cytokine productionPromoting generation of tolerogenic myeloid-derived dendritic cellsSuppressing the production of IgE
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Germany, 2009 Finland, 2010 US, 2011
Hypponen et al. Serum 25-hydroxyvitamin D and
IgE. Allergy 2009
Vahavihu et al. vitamin D balance in skin lesions of
psoriasis and atopic dermatitis. Br JDermatol 2010
Sharief et al. Vitamin D levels and food and
environmental allergies. J Allergy Clin Immunol, 201
1
IgEIgEAD, PsoriasisAD, Psoriasis
Food and Food and pollen allergypollen allergy
Vitamin D and Asthma
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JACI. May 2013
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Mechanism of asthma
AirwayInflammation Airway
Hyperresponsiveness
Airway obstruction
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Inflammatory cell
Inflammatory cell
Inflammatorymediators
Inflammatorymediators
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OBSERVATIONAL STUDIES
Cross-sectional
study
2004:Hypponen et al. 7,648 Finnish adults at 31 yr of ageVitamin D supplementation in the first yearof life was associated with increased riskof asthma (OR, 1.33; 95% CI, 0.97–1.82)29.3% were lost to follow-upNo study visits between 4 and 31 yr of ageLack of serum vitamin D measures in infancy
Ann N Y Acad Sci 2004;1037:84–95
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OBSERVATIONAL STUDIES
Birth cohort study
2011: Cord blood asso. Wheeze not Asthma
2010: reduce risk of wheeze
2009: reduce risk of asthma
2007: reduce risk of recurrent wheeze
Camargo et al: New Zealand, 1105823, 5 yr
Miyake et al: Japan, 1002763, 16-24 mo
Erkkola et al: Finland, 35651669, 5 yr
Devereux et al: Boston, 20001212, 5 yrCamargo et al: Scortland, 21281194, 3yr
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• Relatively short duration from 1.3 to 5 yr• making a diagnosis of asthma
challenging• Significant loss to follow-up (20-70%)• Lack of serum vitamin D measures
during pregnancy or in infancy
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OBSERVATIONAL STUDIES
Devereux et al. Freishtat et al.
• 160 adult in UK• No significant
association between serum vitamin D level and asthma
• Small sample size
• 106 African American subjects 6 to 20 yr of age
• Vitamin D insufficiency or deficiency (<30 ng/ml) was associated with asthma (OR, 42; 95% CI, 4.4–399)
• Small sample size
2010: case-control study
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Newly diagnosed asthma Sensitive only to house dust mites Randomized, double-blind, parallel-group,6-month trial
studying
J ALLERGY CLIN IMMUNOL, MAY 2011
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steroid group; n = 24Budesonide 800 mg/d administered as a dry powder and vitamin D placebo
D3 group; n = 24Budesonide 800 mg/d administered as a dry powder and vitamin D-500 IU cholecalciferol
J ALLERGY CLIN IMMUNOL, MAY 2011
6 months of treatment
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J ALLERGY CLIN IMMUNOL, MAY 2011
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J ALLERGY CLIN IMMUNOL, MAY 2011
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86 children (mean age, 11.7 yr) 36 with STRA 26 with moderate asthma(MA) 24 without asthma (control subjects)
Vitamin D deficiency: serum 25(OH)D < 50 nmol/l
Am J Respir Crit Care Med Vol 184. pp 1342–1349, 2011
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Am J Respir Crit Care Med Vol 184. pp 1342–1349, 2011
28 [22–38] nmol/L
42.5 [29–63] nmol/L
56.5 [45–67] nmol/L
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Am J Respir Crit Care Med Vol 184. pp 1342–1349, 2011
94%
54%
33%
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(A) Percent predicted FEV1 (R = 0.43, P = 0.001)(B) Percent predicted FVC (R = 0.32, P = 0.002)
Am J Respir Crit Care Med Vol 184. pp 1342–1349, 2011
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R = –0.6, P = 0.001
Am J Respir Crit Care Med Vol 184. pp 1342–1349, 2011
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Am J Respir Crit Care Med Vol 184. pp 1342–1349, 2011
R = –0.39, P = 0.001
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Steroids in Asthma: Friend or Foe
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The reported prevalence of SRA ranging from 1 in 1000 to 1 in 10,000 patients with asthma
Represent only a small fraction of the total population of patients with asthma
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Steroid Resistant Asthma
Genetic susceptibilityDefects in glucocorticoid receptor (GR) bindingIncreased expression of the functionally inactive
GR-bActivation of transcription factors (eg, activator
protein 1)Decreased synthesis of immunoregulatory
cytokines, such as IL-10
J Allergy Clin Immunol 2013;132:297-304
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Human CD4+ Tregs secrete high levels of IL-10 when stimulated in the presence of dexamethasone and calcitriol (vitamin D3)
Oral administration of vitamin D3 (0.5 mg/day) for 7days to patients with SRA enhanced ex vivo regulatory T cell response to dexamethasone
The Journal of Clinical Investigation, 2006
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Glucocorticoid resistance (SR)
After 40 mg/day oral prednisolone 14 days FEV1 improve < 15% FEV1 < 75% of predicted
Glucocorticoid sensitivity (SS)
After 40 mg/day oral prednisolone 14 days FEV1 improvement > /= 25%
The Journal of Clinical Investigation, 2006
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Current Opinion in Immunology, 2010
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J Allergy Clin Immunol 2013;132:297-304
Healthy adultsAsthmatic patients had moderate-to-severe
asthma for at least 6 months(on therapy step 3 or 4) prebronchodilator FEV1 < 80% of predicted value and >12%
after 400 mg of short acting bronchodilator
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After a 2-week course of prednisolone at 40 mg/1.73 m2 body surface area
Steroid sensitivity increase in FEV1 of greater than 10% from
baseline. Steroid resistance
less than 10% increase in FEV1 from baseline
J Allergy Clin Immunol 2013;132:297-304
Patients with severe asthma exhibit increased levels of TH17 cytokines, which are not inhibited by steroids
Treatment with 1,25(OH)2D3 significantly reduced both IL-17A and IL-22 levels
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Geace Paul et al. Am J Respir Crit Care Med, 2012
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