An Lehouck, PhD; Chantal Mathieu, MD, PhD; Claudia Carremans, MS; Femke Baeke, PhD; Jan Verhaegen, MD, PhD; Johan Van Eldere, MD, PhD; Brigitte Decallonne, MD, PhD; Roger Bouillon, MD, PhD; Marc Decramer, MD, PhD; Wim Janssens, MD, PhD
Acknowledgment: The authors thank Laboratoires SMB (Brussels, Belgium) for providing the vitamin D and placebo solution.
Grant Support: By the Applied Biomedical Research Program, Agency for Innovation by Science and Technology (IWT-TBM) (G.335102) and Laboratoires SMB (Brussels, Belgium). Drs. Mathieu, Decallonne, and Janssens are supported by Research Foundation–Flanders (FWO Vlaanderen).
Potential Conflicts of Interest: Disclosures can be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=M11-1083.
Reproducible Research Statement:Study protocol: Synopsis available at ClinicalTrials.gov. Statistical code: Available from Dr. Janssens (e-mail, email@example.com). Data set: Not available.
Requests for Single Reprints: Wim Janssens, MD, PhD, Respiratory Medicine, University Hospitals Leuven, Herestraat 49, Bus 7003, 3000 Leuven, Belgium; e-mail, firstname.lastname@example.org.
Current Author Addresses: Dr. Lehouck: Respiratory Medicine, University Hospitals Leuven, UZ Herestraat 49, Bus 7003, 3000 Leuven, Belgium.
Drs. Mathieu, Baeke, Decallonne, and Bouillon: Endocrinology and Experimental Medicine, University Hospitals Leuven, O&N I Herestraat 49, Bus 902, 3000 Leuven, Belgium.
Ms. Carremans and Dr. Janssens: Respiratory Medicine, University Hospitals Leuven, Herestraat 49, Bus 7003, 3000 Leuven, Belgium.
Drs. Verhaegen and Van Eldere: Laboratory of Bacteriology, University Hospitals Leuven, UZ Herestraat 49, Bus 7003, 3000 Leuven, Belgium.
Dr. Decramer: Respiratory Medicine, University Hospitals Leuven, UZ Herestraat 49, Bus 7003, 3000 Leuven, Belgium.
Author Contributions: Conception and design: C. Mathieu, C. Carremans, F. Baeke, J. Van Eldere, B. Decallonne, R. Bouillon, W. Janssens.
Analysis and interpretation of the data: A. Lehouck, C. Mathieu, F. Baeke, B. Decallonne, R. Bouillon, M. Decramer, W. Janssens.
Drafting of the article: A. Lehouck, C. Mathieu, F. Baeke, J. Verhaegen, W. Janssens.
Critical revision of the article for important intellectual content: C. Mathieu, F. Baeke, B. Decallonne, R. Bouillon, M. Decramer, W. Janssens.
Final approval of the article: C. Mathieu, F. Baeke, B. Decallonne, R. Bouillon, M. Decramer, W. Janssens.
Provision of study materials or patients: C. Mathieu, C. Carremans, J. Verhaegen, W. Janssens.
Statistical expertise: A. Lehouck, W. Janssens.
Obtaining of funding: C. Mathieu, M. Decramer, W. Janssens.
Administrative, technical, or logistic support: C. Carremans, F. Baeke, J. Van Eldere.
Collection and assembly of data: A. Lehouck, C. Mathieu, C. Carremans, F. Baeke, J. Verhaegen, J. Van Eldere, W. Janssens.
Lehouck A, Mathieu C, Carremans C, Baeke F, Verhaegen J, Van Eldere J, et al. High Doses of Vitamin D to Reduce Exacerbations in Chronic Obstructive Pulmonary Disease: A Randomized Trial. Ann Intern Med. 2012;156:105-114. doi: 10.7326/0003-4819-156-2-201201170-00004
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Published: Ann Intern Med. 2012;156(2):105-114.
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GoranKrstic, PhD, Human Health Risk Assessment Specialist
January 26, 2012
A functional vitamin D status is more than a simple serum 25-hydroxyvitamin D concentration
Considering that there is evidence in the published literature, as referenced in this article by Lehouck et al. , that low serum 25- hydroxyvitamin D (25-[OH]D or calcidiol) levels are associated with the impaired forced expiratory volume in 1 second (FEV1), and that vitamin D deficiency, defined by the Institute of Medicine as serum 25-[OH]D levels <20 ng/mL, is present in 60% to 75% of patients with severe chronic obstructive pulmonary disease (COPD), it is interesting that vitamin D supplementation does appear to have very little or no effect on the incidence of COPD exacerbations in the studied group of patients. Although the acknowledged small sample size may explain in part the observed absence of a significant effect, it is also important to take into account the uncertainties potentially associated with establishing the vitamin D status on the basis of serum 25-[OH]D rather than the active and functional form of vitamin D (i.e., 1,25[OH]2D or calcitriol). It would be interesting to observe if treatment of the same group of patients with 1,25[OH]2D would show different results.
In addition, some genes and polymorphisms directly or indirectly associated with the function of vitamin D are implicated in the pathogenesis of COPD . Hence, it may be beneficial to focus further research in this field on the genetic polymorphism of loci encoding, for example, the vitamin D-binding protein (VDBP), the vitamin D receptor (VDR), and the enzyme responsible for transforming 25-[OH]D to 1,25[OH]2D, 1-alpha hydroxylase (CYP27B1) . Controlling for these and other vitamin D associated polymorphisms in a larger study group may provide the basis for confirming or ruling out the effects of a functional vitamin D status on the development/exacerbation of COPD.
1. Lehouck A, Mathieu C, Carremans C, Baeke F, Verhaegen J, Van Eldere J et al. High doses of vitamin D to reduce exacerbations in chronic obstructive pulmonary disease: a randomized trial. Ann Intern Med. 2011;155:827-838.
2. Joos L, Par? PD, Sandford AJ. Genetic risk factors of chronic obstructive pulmonary disease. Swiss Med Wkly. 2002;132(3-4):27-37.
3. Holick MF. Vitamin D deficiency. N Engl J Med. 2007;357(3):266-81.
FranciscoRamirez Lafita MD, PhD, FACP, Rheumatologist, Belinda Garcia MD
Clinica Monegal. Tarragona, Spain
January 29, 2012
Vitamin D beyond healthy bones
Interest in extra bone effects of vitamin D have been renewed in the past decade. Vitamin D deficiency is frequently found even in industrialized countries. Recently, the term vitamin D insufficiency has been used to describe suboptimal levels of serum 25(OH)D that could be associated with other disease outcomes (extra-skeletal conditions). Cutoff value for optimal vitamin D status has been established in 30 ng/mL. On this basis, patients can be diagnosis with vitamin D insufficiency or deficiency when most have not evidence of disease1. In a recent publication in Annals, Lehouck et al2 found that high doses of vitamin D supplementation in a sample of patients with COPD failed to reduce the incidence of exacerbations and to improve secondary outcomes such as FEV1, quality of life and death rate. However, in a small sample of 30 patients with severe vitamin D deficiency (serum 25-OH-D levels less of 10 ng/mL) an important reduction of COPD exacerbations per patient-year was observed in the group of only 15 patients supplemented with high doses of vitamin D (p 0.042). Vitamin D deficiency has been linked to accelerated decline in lung function, increased inflammation and reduced immunity in chronic lung diseases. The exact mechanism by which vitamin D plays a protective role on lung health is not clearly underlined but, vitamin D appears to modulate inflammatory and structural cells (dendritic cells, lymphocytes, monocytes, and epithelial cells)3 Recently, some papers on the role of vitamin D receptor (VDR) on lung health have been published. Experimental VDR knock out in mice induced an increased presence of inflammatory cells and mediators (phosphoacetylation of NF-?B and up-regulation of matrix metalloproteinases 2, 9 and 12) as a declining in lung function. 4 More recently, other authors have found that variant in gene polymorphism in VDR, was associated with the development of COPD in men 5. Vitamin D effects on health could be related not only to serum 25(OH)D levels but to an effective signal process on cell receptors. Extra bone effect of vitamin D deserves further studies.
1. Thatcher TD, Clarke BL. Vitamin D insufficiency. Mayo Clin Proc. 2011;86(1):50-60
2. Lehouck A, Mathieu C, Carremans C, Baeke F, Verhaegen J, van Eldere JV, Decallonne B, Boluillon R, Decramer M, Janssens W. High doses of Vitamin D to reduce exacerbations in chronic obstructive pulmonary disease. Ann Intern Med. 2012;156:105-114
3. Greulich HC, Koczulla RA, Meyer S, Zakharkina T, Bransheidt M, Eschmann R, Blas R. The role of vitamin D in pulmonary disease: COPD, asthma, infection and cancer. Respir Res. 2011;12:31
4. Sundar IK, Hwang JW, Wu S, Sun J, Rahman I. Deletion of vitamin D receptors leads to premature emphysema/COPD by increased matrix metalloproneinases and lymphoid aggregates formation. Biochem Biophys Res Commun. 2011;406(1):127-133
5. Poon A, Cho MH, Sparrow D, Litonjua AA. A variant in the vitamin D receptor gene (vdr) is associated with time to the onset of chronic obstructive pulmonary disease in men. Am J Respir Crit Care Med. 2011;183:A2655
Victor O.Kolade, MD, FACP, Meena Sunil, MD
Department of Medicine, University of Tennessee College of Medicine Chattanooga
February 15, 2012
Vitamin D for COPD: Better than the Alternative?
We believe the report of Lehouck et al on Vitamin D supplementation and reduction of exacerbations of chronic obstructive pulmonary disease (COPD) (1) is very timely. Although Vitamin D deficiency has been associated with increasing severity of COPD (2), current guidelines on evaluation of Vitamin D deficiency do not call for screening of persons with most forms of chronic lung disease (3). Indeed, the guidelines do not identify predictors of severe Vitamin D deficiency, in which guideline- appropriate therapy appeared to confer a benefit in terms of reduction of COPD exacerbations, per Lehouck et al; no significant side effects of therapy would be anticipated at the dose used - which is recommended for replacement (3). If these findings are replicated in larger studies, vitamin D supplementation would likely be a safer alternative to daily azithromycin - which has been shown to prevent COPD exacerbations while increasing the risk of hearing loss (4). Additionally, this study should provoke a closer look into the effects of severe Vitamin D deficiency, for which there is yet no consensus definition. ? References
1. Lehouck A, Mathieu C, Carremans C, Baeke F, Verhaegen J, Van Eldere J, et al. High doses of vitamin d to reduce exacerbations in chronic obstructive pulmonary disease: a randomized trial. Ann Intern Med. 2012;156(2):105-14.
2. Janssens W, Bouillon R, Claes B, Carremans C, Lehouck A, Buysschaert I, et al. Vitamin D deficiency is highly prevalent in COPD and correlates with variants in the vitamin D-binding gene. Thorax. 2010;65(3):215-20.
3. Holick MF, Binkley NC, Bischoff-Ferrari HA, Gordon CM, Hanley DA, Heaney RP, et al. Evaluation, treatment, and prevention of vitamin D deficiency: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 2011;96(7):1911-30.
4. Albert RK, Connett J, Bailey WC, Casaburi R, Cooper JA, Criner GJ, et al. Azithromycin for prevention of exacerbations of COPD. N Engl J Med. 2011;365(8):689-98.
Hospital Medicine, Pulmonary/Critical Care, Chronic Obstructive Airway Disease, Prevention/Screening.
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