Vitamin D and Asthma
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Vitamin D and Asthma

Vitamin D and Asthma

Presented by Jaichat Mekaroonkamol, MD.

August30, 2013

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  • Vitamin D comes from two sources: skin exposure to ultraviolet B (UVB) rays and dietary intake. Dietary sources include fish oil, fish, liver, egg yolk and dietary supplements.6,7 As very few foods contain vitamin D, sunlight exposure is the primary determinant of vitamin D status in humans. In a fair skinned person, 20 to 30 minutes of sunlight exposure on the face and forearms at midday is estimated to generate the equivalent of around 2000 IU of vitamin D. Two or three such sunlight exposures a week are sufficient to achieve healthy vitamin D levels in summer in the UK.8 In the absence of adequate sun exposure, at least 800–1000 IU (20–25 mg) vitamin D per day may be needed to achieve t
  • Vitamin D synthesis is initiated in the skin by solar UVB radiation (wavelength 290 to 315 nm), activating the precursor 7- dehydrocholesterol, which then circulates in the bloodstream to the liver, where it is converted into its main metabolite, 25- hydroxyvitamin D (25[OH]D), which has blood levels about 1000 times higher than the active metabolite, 1,25-dihydroxyvitamin D (1,25-[OH]2D. Until recently, it was thought that the conversion to 1,25-(OH)2D occurred only in the kidneys, but increasing evidence indicates that the cells of most organs have the vitamin D receptor (VDR) and the capacity to synthesize 1,25-(OH)2D locally.7 This synthesis of 1,25-(OH)2D is dependent on serum 25(OH)D levels, the primary circulating form of vitamin D.
  • - Vitamin D deficiency is defined by most experts as a 25[OH]D level of less than 50 nmol/L (20 ng per millilitre) - 25[OH]D levels are inversely related to parathyroid hormone levels until the former reach 75 to 100 nmol/L (30–40 ng per millilitre), at which point parathyroid hormone levels begin to level off (at their nadir).13–15 Intestinal calcium transport increases by 45 to 65% when 25[OH]D levels increase from an average of 50 to 80 nmol/L (20 to 32 ng per millilitre).16 25[OH]D levels between 50–75 nmol/L (20–30 ng per millilitre) are considered indicative of vitamin D insufficiency on the basis of the above data and their association with health outcomes.17,18 25[OH]D levels of 75 nmol/L (30 ng per millilitre) to 100 nmol/L, are indicative of normal vitamin D levels.17,19 Excessive levels or vitamin D intoxication are rare
  • Definitions At risk of vitamin D deficiency: Serum 25OHD less than 30 nmol/L (12 ng/mL) ( 1 ). At risk of vitamin D inadequacy: Serum 25OHD 30–49 nmol/L (12–19 ng/mL) ( 1 ). Sufficient in vitamin D: Serum 25OHD 50–125 nmol/L (20–50 ng/mL) ( 1 ). Possibly harmful vitamin D: Serum 25OHD greater than 125 nmol/L (50 ng/mL) ( 1 ). Ref: Institute of Medicine. Dietary reference intakes for calcium and vitamin D. Washington, DC: National Academies Press. 2010.
  • Photochemical synthesis of vitamin D 3 (cholecalciferol, D 3 ) occurs cutaneously where pro-vitamin D 3 (7-dehydrocholesterol) is converted to pre-vitamin D 3 (pre-D 3 ) in response to ultraviolet B (sunlight) exposure. Vitamin D 3 , obtained from the isomerization of pre-vitamin D 3 in the epidermal basal layers or intestinal absorption of natural and fortified foods and supplements, binds to vitamin D-binding protein (DBP) in the bloodstream, and is transported to the liver. D 3 is hydroxylated by liver 25-hydroxylases (25-OHase). The resultant 25-hydroxycholecalciferol (25(OH)D 3 ) is 1-hydroxylated in the kidney by 25-hydroxyvitamin D 3 -1-hydroxylase (1-OHase). This yields the active secosteroid 1,25(OH) 2 D 3 (calcitriol), which has different effects on various target tissues23. The synthesis of 1,25(OH) 2 D 3 from 25(OH)D 3 is stimulated by parathyroid hormone (PTH) and suppressed by Ca 2+ , P i and 1,25(OH) 2 D 3 itself. The rate-limiting step in catabolism is the degradation of 25(OH)D 3 and 1,25(OH) 2 D 3 to 24,25(OH)D 3 and 1,24,25(OH) 2 D 3 , respectively,which occurs through 24-hydroxylation by 25-hydroxyvitamin D 24-hydroxylase (24-OHase), encoded by the CYP24A1 gene. 24,25(OH)D 3 and 1,24,25(OH) 2 D 3 are consequently excreted. The main effects of 1,25(OH) 2 D 3 on various target tissues are highlighted abo
  • Figure 1. kanji Fighting infections with vitamin D. Two related pathways within the skin and circulating monocytes-macrophages are highlighted. Sunlight converts 7-dehydrocholesterol (7-DHC) in the skin to vitamin D3, which is converted successively to 25-hydroxy-D3 (25-D3) and then to 1,25-dihydroxy-D3 (1,25-D3) within keratinocytes. Sunlight also induces expression of the vitamin D receptor (VDR). 1,25-D3 and the VDR then together induce the expression of the gene encoding the human antimicrobial peptide LL-37. Vitamin D3 enters the systemic circulation and is converted to 25-D3 by the liver. Circulating monocytes are activated by TLR2/1 agonists present on specific microbes. The genes encoding VDR and CYP 27B1 are induced. CYP27B1 converts 25-D3 from the circulation to 1,25-D3, joins with the VDR and activates the gene encoding LL-37, leading to an increase in cellular LL-37 and enhanced microbicidal activity of the phagocyte.
  • Schematic model for 1,25D3-regulated innate immune functions in keratinocytes and monocytes. Two distinct 1,25D3-dependent pathways in keratinocytes and monocytes are shown. In skin injury, keratinocytes are activated by TGF-β1 or TLR2/6 ligands, which then leads to induction of CYP27B1. As a consequence 25D3 is converted to 1,25D3, which, upon activation of the VDR, induces cathelicidin, TLR2, and CD14. The 1,25D3-induced TLR2 enables the response of keratinocytes to TLR2 activation, resulting in further increased cathelicidin expression. In contrast, circulating monocytes are activated by TLR2/1 agonists. As a consequence, the genes encoding the VDR and CYP27B1 are induced. CYP27B1 converts 25D3 to 1,25D3 and subsequently increases cathelicidin.
  • Figure 1. Vitamin D and innate immunity. Activation of macrophage TLR (e.g. TLR2) signaling by pathogens such as as Mycobacterium tuberculosis results in the transcriptional induction of VDR and CP27B expression (blue arrows). Circulating 25OHD (red circles) bound to plasma DBP enters macrophages (red arrows) and is converted to 1,25(OH) 2 D (blue circles) by mitochondrial CP27B, and can bind to the VDR in the cell. Once bound to VDR, 1,25(OH) 2 D is able to act as a transcriptional factor leading to the induction of cathelicidin expression (solid purple arrow). Incorporation into phagosomes containing internalized pathogen enables cathelicidin to function as an antibacterial agent. As well as upregulating cathelicidin expression, macrophage synthesis of 1,25(OH) 2 D can also facilitate negative autoregulation (dashed purple arrows), firstly via increased expression of the feedback enzyme CP24A and its decoy CP24A-SV, and secondly via downregulation of TLR expression. In parallel with autocrine effects on innate antibacterial function, macrophage CP27B might also induce paracrine responses in monocytes, and T or B lymphocytes as a consequence of 1,25(OH) 2 D secretion. Abbreviations: 1,25(OH) 2 D, 1,25-dihydroxyvitamin D; 25OHD, 25-hydroxyvitamin D; CP24A, 1,25(OH) 2 D 24-hydroxylase; CP24A-SV, 1,25(OH) 2 D 24-hydroxylase splice variant; CP27B, 25OHD-1 hydroxylase; DBP, vitamin-D-binding protein; TLR, Toll-like receptor 2; VDR, vitamin D receptor.
  • Systemic or locally produced 1,25(OH) 2 VD 3 exerts its effects on several immune-cell types, including macrophages, dendritic cells (DCs), T and B cells. Macrophages and DCs constitutively express vitamin D receptor (VDR), whereas VDR expression in T cells is only upregulated following activation. In macrophages and monocytes, 1,25(OH) 2 VD 3 positively influences its own effects by increasing the expression of VDR and the cytochrome P450 protein CYP27B1. Certain Toll-like-receptor (TLR)-mediated signals can also increase the expression of VDR. 1,25(OH) 2 VD 3 also induces monocyte proliferation and the expression of interleukin-1 (IL-1) and cathelicidin (an antimicrobial peptide) by macrophages, thereby contributing to innate immune responses to some bacteria. 1,25(OH) 2 VD 3 decreases DC maturation, inhibiting upregulation of the expression of MHC class II, CD40, CD80 and CD86. In addition, it decreases IL-12 production by DCs while inducing the production of IL-10. In T cells, 1,25(OH) 2 VD 3 decreases the production of IL-2, IL-17 and interferon- (IFN) and attenuates the cytotoxic activity and proliferation of CD4 + and CD8 + T cells. 1,25(OH) 2 VD 3 might also promote the development of forkhead box protein 3 (FOXP3) + regulatory T (T Reg ) cells and IL-10-producing T regulatory type 1 (T R 1) cells. Finally, 1,25(OH) 2 VD 3 blocks B-cell proliferation, plasma-cell differentiation and immunoglobulin production. ASCs, antibody-secreting cells.
  • In children and adolescents, allergic sensitization to 11 of 17 allergens was more common in those with 25(OH)D deficiency. Compared with sufficient vitamin D levels of >30 ng/ mL, after multivariate adjustment, 25(OH)D levels 0.01. There were no consistent associations seen between 25(OH)D levels and allergic sensitization in adults.
  • Description of studies. Eight studies reported associations with vitamin D18,19,21,24,26,27,31,70 (see this article’s Table E5 in the Online Repository at www.jacionline.org).We found 7 cohort studies. Four cohort studies reported that higher maternal vitamin D intake during pregnancy may decrease the risk of wheezing in early childhood.19,21 Two cohort studies reported on the association between maternal vitamin D intake and childhood asthma at age 5 years, with 1 study reporting no association21 and 1 reporting a beneficial inverse association.24 In contrast, 2 other cohort studies reported adverse associations between maternal blood vitamin D levels during pregnancy or high-dose vitamin D supplementation during infancy and childhood asthma, atopic dermatitis, and/or allergic rhinitis.26,27 Main findings. Pooled analysis of 4 large cohort studies 19,21,24,31 showed that higher maternal vitamin D intake was associated with reduced odds of wheezing (ie, either recurrent wheezing/wheeze in the previous year (OR, 0.56; 95% CI, 0.42-0.73; P < .001; Fig 4). Pooled analysis from 2 studies showed21,24 that maternal vitamin D intake was not associated with asthma in children age 5 years (see this article’s Fig E3 in the Online Repository at www.jacionline.org). We could not undertake meta-analyses for other outcomes. One cross-sectional study found that early-life cod liver oil supplementation was associated with increased atopic sensitization (adjusted OR, 1.78; 95% CI, 1.03-3.07).70 However, this study was problematic in that it did not fully adjust for all relevant confounding factors. Summary of evidence. Overall, the body of evidence from these observational studies was judged to be methodologically weak but supportive of an association between maternal vitamin D intake and childhood wheeze.
  • 97% of children with STRA, 92% of children with MA, and 83% of control subjects had insufficient serum 25(OH)D3 levels [25(OH)D3 level , 75 nmol/L].
  • Positive association between serum vitamin D levels and (A) percent predicted FEV1 (R ¼ 0.43, P , 0.001) and (B) FVC (R ¼ 0.32, P ¼ 0.002). Lower serum vitamin D levels were associated with (C) higher bronchodilator response (BDR) (r ¼ –0.40, P ¼ 0.003) and (D) positive BDR (FEV1 improvement of at least 12%) (P , 0.001). BDR (%) ¼ percentage increase in FEV1 after inhalation of 1,000 mg of salbutamol. Correlation was determined by Spearman rank correlation coefficient. The Mann-Whitney U test was used to compare differences between groups. ***P , 0.001. MA ¼ moderate asthma; STRA ¼ severe therapy- resistant asthma.
  • Positive association between serum vitamin D level and asthma control test (ACT) (r ¼ 0.6, P , 0.001). (A) Children with higher serum vitamin D levels had fewer asthma-related symptoms. Correlation was determined by Spearman rank correlation coefficient. (B) Children with lower serum vitamin D levels had more acute exacerbations in the last 6 months. Lower serum vitamin D levels were associated with increased (B) oral and (C) inhaled corticosteroid (ICS) use. The Kruskal- Wallis test and Mann-Whitney U test, followed by a Bonferroni correction, were used to compare differences between groups. **P , 0.01; ***P , 0.001. BDP ¼ beclomethasone dipropionate; MA ¼ moderate asthma; STRA ¼ severe therapy- resistant asthma.
  • Positive association between serum vitamin D level and asthma control test (ACT) (r ¼ 0.6, P , 0.001). (A) Children with higher serum vitamin D levels had fewer asthma-related symptoms. Correlation was determined by Spearman rank correlation coefficient. (B) Children with lower serum vitamin D levels had more acute exacerbations in the last 6 months. Lower serum vitamin D levels were associated with increased (B) oral and (C) inhaled corticosteroid (ICS) use. The Kruskal- Wallis test and Mann-Whitney U test, followed by a Bonferroni correction, were used to compare differences between groups. **P , 0.01; ***P , 0.001. BDP ¼ beclomethasone dipropionate; MA ¼ moderate asthma; STRA ¼ severe therapy- resistant asthma.
  • Significant associations between serum vitamin D status and responsiveness to corticosteroids in the pediatric but not the adult asthma group.
  • five genes or gene complexes (ADAM33, PHF11, DPP10, GPRA and SPINK5) have been linked with predisposition to asthma (reviewed by Cookson and Moffatt 2004),
  • We show here that administration of vitamin D3 to healthy individuals and SR asthmatic patients enhanced subsequent responsiveness to dexamethasone for induction of IL-10. This strongly suggests that vitamin D3 could potentially increase the therapeutic response to glucocorticoids in SR patients
  • 7 SR patients (2 female, 5 male; mean age ± SD, 54 ± 15; mean basal FEV1, 55% ± 20% of Predicted 5 SS patients (2 female, 3 male; mean age, 50 ± 10; mean basal FEV1, 46% ± 24% of predicted
  • T helper 17 (T H 17) cells are a newly described subset of CD4 + T cells that may have a role in chronic obstructive pulmonary disease (COPD) and severe asthma. These cells release interleukin-17 (IL-17) and IL-17F, which act on airway epithelial cells to release CXC-chemokine ligand 1 (CXCL1) and CXCL8, which attract neutrophils, and IL-6 , which enhances the activation of T H 17 cells. T H 17 cells also release IL-21, which promotes T H 17-cell differentiation via a positive autoregulatory loop involving the transcription factor STAT3 (signal transducer and activator of transcription 3) and IL-22, which induces the release of IL-10 and acute-phase proteins. The regulation of T H 17 cells is predominantly via IL-23 through the activation of the transcription factor retinoic-acid-receptor-related orphan receptor-t (RORt), whereas transforming growth factor- (TGF) may have an inhibitory effect in human cells. TNF, tumour-necrosis factor.
  • A long standing paradigm is that antigen-specific Th2 cells and their cytokines such as IL-4, IL-5, and IL-13 orchestrate the characteristic features of atopic allergy. The discovery of a role for IL-17-producing (Th17) and IL-22-producing (Th22) T helper cells in inflammatory diseases has added an additional layer of complexity to the understanding of the pathogenesis of allergic diseases. Here we re-evaluate the role of T helper cells, with special focus on the Th17 and Th22 subsets in allergic asthma and atopic dermatitis. Whereas sparse data point to a protective role of the increasing amounts of Th22 cells that are found in chronic stages of both allergies, the data on Th17 cells paint different pictures for the contribution of Th17 cells during subsequent stages of these two forms of allergy. Figure 1. Th17 and Th22 cells in allergic asthma and atopic dermatitis. Both allergies are characterized by a Th2-dominated cytokine milieu and evolve from an initial acute phase to a more severe/chronic phase. In allergic asthma, IL-17 and neutrophilia arise with increasing severity of disease, while IL-17 is absent in chronic lesions of AD. Otherwise, both chronic allergic asthma and chronic AD inflammation are characterized by elevated amounts of IL-22.

Vitamin D and Asthma Vitamin D and Asthma Presentation Transcript

  • 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 systemLOGO
  • 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 indicator There are no consensus guidelines available on optimal levels of serum 25[OH]D Mayo Clin Proc 2006 Am J Clin Nutr 2006 N 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 immune system 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%CI)ofPT 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%CIcalcidiol)(ng/ml) 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 prevalenceofvitaminDinadequacy(%) Pre-menwomen Earlypost-men Urbanizedelderly Ruralelderly 77.98% 60% 65.4% 15.4% Pre-men.women Earlypost-men Urbanizedelderly Ruralelderly
  • 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 1.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 epidermal lipid 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
  • AssociationsAssociations of vitamin Dof vitamin D with allergicwith allergic diseasedisease
  • Vitamin D and Allergic disease Promote immune tolerance Promoting development and increased activity of regulatory T cell Regulating cytokine production Promoting generation of tolerogenic myeloid- derived dendritic cells Suppressing 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 J Dermatol 2010 Sharief et al. Vitamin D levels and food and environmental allergies. J Allergy Clin Immunol, 2011 IgEIgE AD, PsoriasisAD, Psoriasis Food andFood and pollen allergypollen allergy Vitamin D and Asthma
  • JACI. May 2013
  • Mechanism of asthma Airway Inflam mation Airway Hyperrespo nsiveness Airway obstruction
  • Inflammatory cell Inflammatory cell Inflammatory mediators Inflammatory mediators
  • OBSERVATIONAL STUDIES Cross- sectional study 2004:Hypponen et al. 7,648 Finnish adults at 31 yr of age Vitamin D supplementation in the first year of life was associated with increased risk of asthma (OR, 1.33; 95% CI, 0.97–1.82) 29.3% were lost to follow-up No study visits between 4 and 31 yr of age Lack 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, 1105823, 5 yr Miyake et al: Japan, 1002763, 16-24 mo Erkkola et al: Finland, 35651669, 5 yr Devereux et al: Boston, 20001212, 5 yr Camargo et al: Scortland, 21281194, 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 = 24 Budesonide 800 mg/d administered as a dry powder and vitamin D placebo D3 group; n = 24 Budesonide 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 susceptibility Defects in glucocorticoid receptor (GR) binding Increased expression of the functionally inactive GR-b Activation 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 adults Asthmatic 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
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