vitamin d and asthma

COMPANY NAME

Vitamin D and AsthmaVitamin D and Asthma

Jaichat Mekaroonkamol MD.

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

Vitamin D metabolism and physiology

• Sources of vitamin D• Vitamin D metabolism• Definition of vitamin D

deficiency and insufficiency

Sources of vitamin D

Holick MF. Vitamin D deficiency. N Engl J Med 2007;357:266–81.

Holick MF. Vitamin D deficiency. N Engl J Med 2007;357:266–81.

Vitamin D metabolism

Holick MF. Vitamin D deficiency. N Engl J Med 2007;357:266–81.

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)

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

Definition

Who is at risk

A. Gupta et al. / Paediatric Respiratory Reviews 13 (2012) 236–243.

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.

Vitamin D Status: United States, 2001–2006. CDC March 2011

Vitamin D Status: United States, 2001–2006. CDC March 2011

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

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

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

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

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

Chailurkit et al. BMC Public Health 2011

Chailurkit et al. BMC Public Health 2011

Chailurkit et al. BMC Public Health 2011

Vitamin D inadequate

45.2%

Vitamin D deficiency

5.7%

COMPANY NAME

Roles of Vitamin D

Calcium homeostasis

Immunomodulator

J Allergy Clin Immunol 2013;131:324-9

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

Immunomodulator

1.Increasing antimicrobial action Cathelicidin

2.Decrease inflammation

IL-10 secreting Treg

J Allergy Clin Immunol 2013;131:324-9

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

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

Nature Clinical Practice Endocrinology & Metabolism, 2008

Immunomodulator

J Allergy Clin Immunol 2013;131:324-9

• Vitamin D induces cathelicidin• cathelicidin was required for

cytotoxic activity of natural killer cells

Immunomodulator

J Allergy Clin Immunol 2013;131:324-9

Decreased expression of TLRs and suppressed TLR-mediated

inflammation

Immunomodulator

J Allergy Clin Immunol 2013;131:324-9

• Decreased immune receptor expression on dendritic cells (DCs)

• Inhibited DC activation by LPS

Immunomodulator

J Allergy Clin Immunol 2013;131:324-9

Immunomodulator

J Allergy Clin Immunol 2013;131:324-9

Immunomodulator

J Allergy Clin Immunol 2013;131:324-9

Immunomodulator

J Allergy Clin Immunol 2013;131:324-9

Associations Associations of vitamin D of vitamin D with allergic with allergic

diseasedisease

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

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

JACI. May 2013

Mechanism of asthma

AirwayInflammation Airway

Hyperresponsiveness

Airway obstruction

Inflammatory cell

Inflammatory cell

Inflammatorymediators

Inflammatorymediators

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

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

• 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

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

Newly diagnosed asthma Sensitive only to house dust mites Randomized, double-blind, parallel-group,6-month trial

studying

J ALLERGY CLIN IMMUNOL, MAY 2011

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

J ALLERGY CLIN IMMUNOL, MAY 2011

J ALLERGY CLIN IMMUNOL, MAY 2011

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

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

Am J Respir Crit Care Med Vol 184. pp 1342–1349, 2011

94%

54%

33%

(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

R = –0.6, P = 0.001

Am J Respir Crit Care Med Vol 184. pp 1342–1349, 2011

Am J Respir Crit Care Med Vol 184. pp 1342–1349, 2011

R = –0.39, P = 0.001

Steroids in Asthma: Friend or Foe

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

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

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

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

Current Opinion in Immunology, 2010

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

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

Geace Paul et al. Am J Respir Crit Care Med, 2012

COMPANY NAME

Thank You!