Vitamin D ReferencesEur J Clin Nutr. 2004 Apr;58(4):563-7.Association of subclinical vitamin D deficiency with severe acute lowerrespiratory infection in Indian children under 5 y.Wayse V, Yousafzai A, Mogale K, Filteau S.SourceCentre for International Child Health, Institute of Child Health, University CollegeLondon, London, UK.AbstractOBJECTIVES:To determine whether subclinical vitamin D deficiency in Indian children under 5 y of ageis a risk factor for severe acute lower respiratory infection (ALRI).DESIGN:A hospital-based case-control study.SETTING:Sanjeevani Paediatrics Hospital, a private hospital in Indapur, India.PARTICIPANTS:A total of 150 children including 80 cases and 70 controls, aged 2-60 months, wereenrolled. Case definition of severe ALRI as given by the World Health Organization wasused for cases. Controls were healthy children attending outpatients service forimmunization.MAIN OUTCOME MEASURE:Association of serum 25-hydroxyvitamin D3 (25OHD3) with severe ALRI, controlling fordemographic and other potential risk factors.RESULTS:Serum 25OHD3 increased with age. Factors significantly associated with decreased riskof severe ALRI in univariate analysis were: exclusive breastfeeding in the first 4 months(cases 35/78 (45%), controls 41/64 (64%); P=0.02); introduction of other dietaryliquids than milk only after 6 months (cases 46/70 (66%), controls 31/66 (47%);P=0.03); use of liquid petroleum cooking fuel (cases 32/80 (40%), controls 40/70(57%); P=0.04); infant not covered in swaddling cloths when exposed to sunlight beforecrawling (cases 11/52 (21%), controls 25/54 (46%); P=0.006); and serum25OHD3>22.5 nmol/l (cases 16/80 (20%), controls 48/70 (69%); P<0.001). Inmultivariate analysis, factors associated with significantly lower odds ratio for havingsevere ALRI were: serum 25OHD3>22.5 nmol/l (OR: 0.09; 95% CI 0.03-0.24; P<0.001)and exclusive breastfeeding in the first 4 months of life (OR 0.42; 95% CI 0.18-0.99;P=0.046) with age and height/age as significant covariates.CONCLUSION:Subclinical vitamin D deficiency and nonexclusive breastfeeding in the first 4 months oflife were significant risk factors for severe ALRI in Indian children.
Pediatrics. 2012 Aug 6. [Epub ahead of print]Vitamin D Deficiency in Critically Ill Children.Madden K, Feldman HA, Smith EM, Gordon CM, Keisling SM, Sullivan RM, HollisBW, Agan AA, Randolph AG.SourceaDivision of Critical Care Medicine, Department of Anesthesia, Perioperative and PainMedicine.AbstractOBJECTIVE:Vitamin D influences cardiovascular and immune function. We aimed to establish theprevalence of vitamin D deficiency in critically ill children and identify factors influencingadmission 25-hydroxy vitamin D (25(OH)D) levels. We hypothesized that levels wouldbe lower with increased illness severity and in children with serious infections.METHODS:Participants were 511 severely or critically ill children admitted to the PICU fromNovember 2009 to November 2010. Blood was collected near PICU admission andanalyzed for 25(OH)D concentration by using Diasorin radioimmunoassay.RESULTS:We enrolled 511 of 818 (62.5%) eligible children. The median 25(OH)D level was 22.5ng/mL; 40.1% were 25(OH)D deficient (level <20 ng/mL). In multivariate analysis, ageand race were associated with 25(OH)D deficiency; summer season, vitaminD supplementation, and formula intake were protective; 25(OH)D levels were not lowerin the 238 children (46.6%) admitted with a life-threatening infection, unless they hadseptic shock (n = 51, 10.0%) (median 25(OH)D level 19.2 ng/mL; P = .0008). Afteradjusting for factors associated with deficiency, lower levels were associated with higheradmission day illness severity (odds ratio 1.19 for a 1-quartile increase in Pediatric Riskof Mortality III score per 5 ng/mL decrease in 25(OH)D, 95% confidence interval 1.10-1.28; P < .0001).CONCLUSIONS:We found a high rate of vitamin D deficiency in critically ill children. Given the rolesof vitamin D in bone development and immunity, we recommend screening of thosecritically ill children with risk factors for vitamin D deficiency and implementation ofeffective repletion strat
Eur J Clin Nutr. 2012 Jul 18. doi: 10.1038/ejcn.2012.82. [Epub ahead of print]Impact of vitamin D supplementation on markers of inflammation in adultswith cystic fibrosis hospitalized for a pulmonary exacerbation.Grossmann RE, Zughaier SM, Liu S, Lyles RH, Tangpricha V.SourceNutrition Health Sciences Program, Emory Graduate Division of Biological and BiomedicalSciences, Emory University, Atlanta, GA, USA.AbstractPatients with cystic fibrosis (CF) suffer from chronic lung infection and inflammationleading to respiratory failure. Vitamin D deficiency is common in patients with CF, andcorrection of vitamin D deficiency may improve innate immunity and reduceinflammation in patients with CF. We conducted a double-blinded, placebo-controlled,randomized clinical trial of high-dose vitamin D to assess the impact of vitaminD therapy on antimicrobial peptide concentrations and markers of inflammation. Werandomized 30 adults with CF hospitalized with a pulmonary exacerbation to 250 000 IUof cholecalciferol or placebo, and evaluated changes in plasma concentrations ofinflammatory markers and the antimicrobial peptide LL-37 at baseline and 12 weekspost intervention. In the vitamin D group, there was a 50.4% reduction in tumornecrosis factor-α (TNF-α) at 12 weeks (P<0.01), and there was a trend for a 64.5%reduction in interleukin-6 (IL-6) (P=0.09). There were no significant changes in IL-1β,IL-8, IL-10, IL-18BP and NGAL (neutrophil gelatinase-associated lipocalin). We concludethat a large bolus dose of vitamin D is associated with reductions in two inflammatorycytokines, IL-6 and TNF-α. This study supports the concept that vitamin D may helpregulate inflammation in CF, and that further research is needed to elucidate thepotential mechanisms involved and the impact on clinical outcomes.European Journal ofClinical Nutrition advance online publication,
Cytokine. 2012 Jul 14. [Epub ahead of print]Effect of vitamin D(3) on chemokine expression in pulmonary tuberculosis.Selvaraj P, Harishankar M, Singh B, Banurekha VV, Jawahar MS.SourceDepartment of Immunology, National Institute for Research in Tuberculosis, FormerlyTuberculosis Research Centre, Indian Council of Medical Research, 1, SathyamoorthyRoad, Chennai 600 031, India.Abstract1,25 Dihydroxy vitamin D(3) (vitamin D(3)) is an immunomodulator and its deficiencyhas been associated with susceptibility to tuberculosis. We have studied theimmunoregulatory role of vitamin D(3) on various chemokine expression in pulmonarytuberculosis. Peripheral blood mononuclear cells obtained from 21 pulmonarytuberculosis (PTB) patients and 24 healthy controls (HCs) were cultured for 48h withculture filtrate antigen (CFA) of Mycobacterium tuberculosis with or without vitamin D(3)at a concentration 1×10(-7)M. The relative mRNA expression of monocytechemoattractant protein-1 (MCP-1, CCL2), macrophage inflammatory protein-1α (MIP-1α, CCL3), macrophage inflammatory protein-1β (MIP-1β, CCL4), and regulated upon-activation, normal T cell-expressed and secreted (RANTES, CCL5) and IFN-γ inducibleprotein-10 (IP-10, CXCL10) chemokines were estimated from 48h old macrophagesusing real-time polymerase chain reaction (RT-PCR). The culture supernatants wereused to estimate the various chemokines including monokine induced by IFN-γ (MIG,CXCL9) levels using cytometric bead array. In HCs, vitamin D(3) significantly suppressedthe MCP-1 mRNA expression of CFA stimulated cells (p=0.0027), while no such effectwas observed in PTB patients. Vitamin D(3) showed no significant effect on MIP-1α, MIP-1β and RANTES in both the study groups. The CFA induced IP-10 mRNA and proteinexpression was significantly suppressed by vitamin D(3) in both the study groups(p<0.05). A similar suppressive effect of vitamin D(3) was observed with MIG protein inhealthy controls (p=0.0029) and a trend towards a suppression was observed in PTBpatients. The suppressive effect of vitamin D(3) is more prominent in CXC chemokinesrather than CC chemokines. This suggests that vitamin D(3) may down regulate therecruitment and activation of T-cells through CXC chemokines at the site of infection andmay act as a potential anti-inflammatory agent.
J Proteomics. 2012 Jul 6. [Epub ahead of print]Vitamin D binding protein isoforms as candidate predictors of diseaseextension in childhood arthritis.Gibson DS, Newell K, Evans AN, Finnegan S, Manning G, Scaife C, McAllisterC, Pennington SR, Duncan MW, Moore TL, Rooney ME.SourceArthritis Research Group, Queens University of Belfast, Centre for Infection andImmunity, Health Sciences Building 97 Lisburn Road, Belfast, BT9 7BL, UK; Division ofEndocrinology, Metabolism and Diabetes, School of Medicine, University of ColoradoDenver, 12800 E. 19th Ave., Aurora, CO 80045, USA.AbstractINTRODUCTION.: Juvenile idiopathic arthritis (JIA) comprises a poorly understood groupof chronic autoimmune diseases with variable clinical outcomes. We investigatedwhether the synovial fluid (SF) proteome could distinguish a subset of patients in whomdisease extends to affect a large number of joints. METHODS.: SF samples from 57patients were obtained around time of initial diagnosis of JIA, labeled with Cy dyes andseparated by two-dimensional electrophoresis. Multivariate analyses were used to isolatea panel of proteins which distinguish patient subgroups. Proteins were identified usingMALDI-TOF mass spectrometry with expression verified by immunochemical methods.Protein glycosylation status was confirmed by hydrophilic interaction liquidchromatography. RESULTS.: A truncated isoform of vitamin D binding protein (VDBP) ispresent at significantly reduced levels in the SF of oligoarticular patients at risk ofdisease extension, relative to other subgroups (p<0.05). Furthermore, sialylated formsof immunopurified synovial VDBP were significantly reduced in extended oligoarticularpatients (p<0.005). CONCLUSION.: Reduced conversion of VDBP to a macrophageactivation factor may be used to stratify patients to determine risk of disease extensionin JIA patients.
Br J Nutr. 2012 Apr 3:1-4. [Epub ahead of print]Prevalence and severity of vitamin D deficiency in patients with diabeticfoot infection.Tiwari S, Pratyush DD, Gupta B, Dwivedi A, Chaudhary S, Rayicherla RK, GuptaSK, Singh SK.SourceDepartment of Endocrinology and Metabolism, Institute of Medical Sciences, BanarasHindu University, Varanasi 221005, UP, India.AbstractThe aim of the present research was to study the prevalence and severity of vitaminD deficiency in patients with diabetic foot infection. Patients were enrolled in two groups:diabetic patients with foot infection (n 125) as cases and diabetic patients withoutthe infection as controls (n 164). Serum 25-hydroxyvitamin D (25(OH)D) was measuredby RIA. Data were presented as means and standard deviations unless otherwiseindicated and were analysed by SPSS. Results revealed that 25(OH)D (nmol/l) wassignificantly lower (40·25 (sd 38·35) v. 50·75 (sd 33·00); P < 0·001) in cases than incontrols. Vitamin D inadequacy (25(OH)D < 75 nmol/l) was equally common in casesand controls (OR 1·45, 95 % CI 0·8, 3·0; P = 0·32), but cases had a greater riskof vitamin D deficiency (25(OH)D < 50 nmol/l) than controls (OR 1·8, 95 % CI 1·1, 3·0;P = 0·02). Risk of severe vitamin Ddeficiency (25(OH)D < 25 nmol/l) was significantlyhigher in cases than in controls (OR 4·0, 95 % CI 2·4, 6·9; P < 0·0001). Age, durationof diabetes and HbA1c were significantly higher in cases than in controls and thereforeadjusted to nullify the effect of these variables, if any, on study outcome. The studyconcluded that vitamin D deficiency was more prevalent and severe in patients withdiabetic foot infection. This study opens up the issue of recognising severe vitaminD deficiency ( < 25 nmol/l) as a possible risk factor for diabetic foot infections and theneed for vitamin D supplementation in such patients for a better clinical outcome. Thiscould be substantiated by similar data from future studies.
Review of infectious diseases vitamin D trials – Feb 2012Current data support vitamin D intervention for tuberculosis and viral respiratory tractinfectionsTranslating the role of vitamin D(3) in infectious diseases.Crit Rev Microbiol. 2012 Feb 5.Khoo AL, Chai L, Koenen H, Joosten I, Netea M, van der Ven A.Radboud University Nijmegen Medical Center, Department of Laboratory Medicine,Laboratory Medical Immunology , Nijmegen , Netherlands.Vitamin D(3) affects both the innate as well as adaptive immune responses.Epidemiological studies have established that vitamin D(3) deficiency plays an importantrole in tuberculosis (TB) and viral influenza prevalence as well as susceptibility to activedisease in TB. Vitamin D(3) status has been associated with the clinical course of HIVinfection and drug interaction with anti-retroviral therapy.This article reviews the immunomodulatory capacity of vitamin D(3) and examines theimpact of vitamin D(3) supplementation as a preventive or therapeutic intervention withthe intent to uncover its potential therapeutic application in infectious diseases and toidentify novel areas for future research.We present a review of randomized, controlled clinical studies conducted in humanswhich included assessment of the immune function or clinical outcome as study endpoints.Current data support vitamin D(3) supplementation as risk-modifying interventionin tuberculosis and viral respiratory tract infection, but the optimal dosageregimen remains to be determined.However, to date the knowledge on its role in fungal infection and sepsis is limitedalthough a potential benefit could be harnessed from its ability to curtail theunrestrained pro-inflammatory response and therefore prevent excessive collateraltissue damage.
The Lancet, Volume 379, Issue 9824, Pages 1373 - 1375, 14 April 2012This article can be found in the following collections: Global Health; PublicHealth; Infectious Diseases (Paediatric infections); Nutrition &Metabolism (Undernutrition, Nutrition & metabolism-other); Paediatrics (Paediatricinfections, Paediatric respiratory medicine); Respiratory Medicine (Paediatric respiratorymedicine)Published Online: 10 April 2012Bolus-dose vitamin D and prevention of childhood pneumoniaAdrian R Martineau aVitamin D deficiency is highly prevalent in children in southern Asia,1 where anassociation with susceptibility to pneumonia—the leading cause of child mortality in theregion2—has been reported.3, 4 Oral boluses of vitamin D induce large and rapid rises incirculating concentrations of calcifediol, the major circulating vitamin D metabolite,which supports broad-spectrum innate immune responses to microbes in vitro.5 Thecase to undertake trials of bolus-dose vitamin D supplementation for pneumoniaprevention in this setting is therefore compelling. In The Lancet, Semira Manaseki-Holland and colleagues6 report results of such a trial, but show no beneficial effect. Theyrandomly assigned 3046 infants aged 1—11 months in Kabul, Afghanistan, to receive aquarterly dose of 2·5 mg (100 000 IU) colecalciferol or placebo over 18 months. VitaminD supplementation did not affect the incidence of first episodes of pneumonia (incidencerate ratio 1·05, 95% CI 0·88—1·25); indeed, an excess of repeat episodes of pneumoniawas recorded in the intervention group (0·06 vs 0·04 episodes per child per year).Does this result spell the end for the hypothesis that vitamin D supplementation mightprevent pneumonia? Certainly the trial has important strengths: it is the largest toassess this question published so far; power calculation assumptions regarding lowbaseline vitamin D status and high pneumonia incidence in the study population werefulfilled; and the dose of vitamin D given was generous. The interpretation that thehypothesis is flawed must therefore be considered. However, the possibility remains thatinvestigation of a different dosing regimen of vitamin D in a different population mightyet yield a positive result.The first reason to consider this possibility relates to the pharmacokinetics of calcifediolresponse to quarterly administration of large bolus doses of vitamin D to infants. Thisresulted in a rapid increase in circulating calcifediol concentrations—tosupraphysiological concentrations in some cases—with a subsequent slow decline to
concentrations similar to those recorded in unsupplemented children.6 Such peaks andtroughs could have potentially deleterious effects on the immune response:concentrations of calcifediol greater than 140 nmol/L have been associated withimpaired immunity to infection,6 possibly related to the fact that vitamin D can suppressadaptive responses to infection as well as boosting innate responses.7 Moreover, chronicexposure to falling calcifediol concentrations has been postulated to cause an imbalancebetween the activity of enzymes that synthesise and catabolise calcitriol in extra-renaltissues, resulting in reduced concentrations of this active metabolite at sites ofdisease.8 Either or both of these events could have contributed to the excess ofrecurrent pneumonia recorded in the intervention group of the study. Giving lower dosesof vitamin D more often could induce sustained elevation of calcifediol concentrationsinto the physiological range; this might have more favourable effects on immunefunction.The second issue to be considered relates to the generalisability of study results.Malnutrition was common in the study population: more than one in six participantshad Z scores of weight-for-age of less than −2. Participants might therefore have beenat high risk of deficiencies in other micronutrients such as calcium and vitamin A, both ofwhich could modify effects of vitamin D supplementation; results of this study cannotnecessarily be applied to better nourished populations. Caution should also be exercisedin extrapolating results of this study to older children: pulmonary expression of patternrecognition receptors is reduced in early life, and responses to their ligation areattenuated.9 The ability of calcifediol to support innate antimicrobial responses in vitro isdependent on the expression of such receptors;5 consequently vitamin Dsupplementation might be more effective at enhancing immune function in older childrenthan in infants.A third explanation for the lack of benefit reported in this trial relates to the possibilitythat a subgroup of participants might have benefited from vitamin D supplementation,but that this effect was obscured by a larger group of less responsive participants.Protective effects might have been restricted to those with profound deficiency, asrecently reported in a trial of vitamin D supplementation in adults with chronicobstructive pulmonary disease;10 alternatively, genetic variation in pathways of vitaminD metabolism, transport, or signalling could have modified the effects of vitamin Dstatus on immunity to respiratory pathogens, as previously shown fortuberculosis.11, 12 Understanding such effect modification has clinical relevance whereresources are sufficient to establish the phenotype and genotype of patients in detail,but they are of more academic interest in low-resource settings where incidence ofchildhood pneumonia is highest. Doing a pragmatic trial to assess effectiveness of bolusvitamin D dosing in a population with high prevalence of deficiency and high incidence of
pneumonia was therefore a logical point of departure, and the negative outcome of thisstudy is important—not because it definitively excludes a role for vitamin Dsupplementation in pneumonia prevention, but because it informs the design of futurestudies. Further trials of more frequent dosing regimens in other age groups with lowerrates of malnutrition, characterising potential effect modifiers such as baseline vitamin Dstatus and genetic factors, are now indicated.I am supported by a National Institute of Health Research (NIHR) programme grant onvitamin D supplementation to prevent acute respiratory illness. I declare that I have noconflicts of interest.References1 Arabi A, El Rassi R, El-Hajj , Fuleihan G. Hypovitaminosis D in developing countries—prevalence, risk factors and outcomes. NatRev Endocrinol 2010; 6: 550-561. CrossRef | PubMed2 Black RE, Cousens S, Johnson HL, et al. Global, regional, and national causes of child mortality in 2008: a systematicanalysis.Lancet 2010; 375: 1969-1987. Summary | Full Text | PDF(1713KB) | CrossRef | PubMed3 Wayse V, Yousafzai A, Mogale K, Filteau S. Association of subclinical vitamin D deficiency with severe acute lower respiratoryinfection in Indian children under 5 y. Eur J Clin Nutr 2004; 58: 563-567. CrossRef | PubMed4 Roth DE, Shah R, Black RE, Baqui AH. Vitamin D status and acute lower respiratory infection in early childhood in Sylhet,Bangladesh. Acta Paediatr 2010; 99: 389-393. CrossRef | PubMed5 Liu PT, Stenger S, Li H, et al. Toll-like receptor triggering of a vitamin D-mediated human antimicrobialresponse. Science2006; 311: 1770-1773. CrossRef | PubMed6 Manaseki-Holland S, Maroof Z, Bruce J, et al. Effect on the incidence of pneumonia of vitamin D supplementation by quarterlybolus dose to infants in Kabul: a randomised controlled superiority trial. Lancet 201210.1016/S0140-6736(11)61650-4. publishedonline April 10. PubMed7 Nielsen NO, Skifte T, Andersson M, et al. Both high and low serum vitamin D concentrations are associated with tuberculosis: acase-control study in Greenland. Br J Nutr 2010; 104: 1487-1491. CrossRef | PubMed8 Vieth R. How to optimize vitamin D supplementation to prevent cancer, based on cellular adaptation and hydroxylaseenzymology. Anticancer Res 2009; 29: 3675-3684. PubMed9 Levy O. Innate immunity of the newborn: basic mechanisms and clinical correlates. Nat Rev Immunol 2007; 7: 379-390. PubMed10 Lehouck A, Mathieu C, Carremans C, et al. High doses of vitamin D to reduce exacerbations in chronic obstructive pulmonarydisease: a randomized trial. Ann Intern Med 2012; 156: 105-114. PubMed11 Martineau AR, Leandro AC, Anderson ST, et al. Association between Gc genotype and susceptibility to TB is dependent on vitaminD status. Eur Respir J 2010; 35: 1106-1112. CrossRef | PubMed
12 Martineau AR, Timms PM, Bothamley GH, et al. High-dose vitamin D3 during intensive-phase antimicrobial treatment ofpulmonary tuberculosis: a double-blind randomised controlled trial. Lancet 2011; 377: 242-250Vit D supplementation cuts respiratory infection riskANI Aug 21, 2012, 01.06PM IST(Vitamin D supplementation…)Daily intake of vitamin D supplement can reduce the risk of respiratory infections suchas colds or flu among children in winter, researchers have suggested.In a study conducted in Mongolian schoolchildren, an international research team foundthat daily vitamin D supplementation decreased the risk of respiratory infections amongchildren who had low blood levels of vitamin D at the start of the study."Our randomized controlled trial shows that vitamin D has important effects on infectionrisk," said Carlos Camargo, MD, of Massachusetts General Hospital (MGH), the studyscorresponding author."In almost 250 children with low blood levels of vitamin D during winter, we found thattaking a daily vitamin D supplement cut in half the risk of a respiratory infection,"Camargo stated.Several recent investigations have suggested that vitamin D - best known for its role inthe development and maintenance of strong bones - has additional important roles,including in immune function.Since vitamin D is naturally produced by the body in response to sunlight, maintainingadequate levels in winter is particularly challenging in areas such as the northern U.S.andCanada that have significant seasonal variations in daily sunlight.The current study analyzed data from the Blue Sky Study, conducted inUlaanbaatar,Mongolia, by a team led by Harvard investigators in collaboration with localhealth researchers.Mongolians are known to be at high risk for vitamin D deficiency, especially duringwinter, and the Blue Sky Study followed schoolchildren, all of whom were found to havelow blood levels of 25-hydroxyvitamin D (25OHD), which is considered the best measureof vitamin D status, at the studys outset.In the current study, Camargo and colleagues compared the number of winterrespiratory infections among a group of children who received daily doses of vitamin Dadded to locally produced milk with that of a control group receiving the same milkwithout added vitamin D.Based on reports from their parents, the children receiving vitamin D had about half theincidence of respiratory infections that the control group had."Our study design provides strong evidence that the association between low vitamin Dand respiratory infections is causal and that treating low vitamin D levels in children withan inexpensive and safe supplement will prevent some respiratory infections," saysCamargo, a professor of Medicine at Harvard Medical School.The findings will appear in the journal Pediatrics.
Original Investigation | February 2009Association Between Serum 25-Hydroxyvitamin D Level and Upper RespiratoryTract Infection in the Third National Health and Nutrition ExaminationAdit A. Ginde, MD, MPH; Jonathan M. Mansbach, MD; Carlos A. Camargo, Jr, MD, DrPHArch Intern Med. 2009;169(4):384-390.ABSTRACTBackground Recent studies suggest a role for vitamin D in innate immunity, includingthe prevention of respiratory tract infections (RTIs). We hypothesize that serum 25-hydroxyvitamin D (25[OH]D) levels are inversely associated with self-reported recentupper RTI (URTI).Methods We performed a secondary analysis of the Third National Health and NutritionExamination Survey, a probability survey of the US population conducted between 1988and 1994. We examined the association between 25(OH)D level and recent URTI in18 883 participants 12 years and older. The analysis adjusted for demographics andclinical factors (season, body mass index, smoking history, asthma, and chronicobstructive pulmonary disease).Results The median serum 25(OH)D level was 29 ng/mL (to convert to nanomoles perliter, multiply by 2.496) (interquartile range, 21-37 ng/mL), and 19% (95% confidenceinterval [CI], 18%-20%) of participants reported a recent URTI. Recent URTI wasreported by 24% of participants with 25(OH)D levels less than 10 ng/mL, by 20% withlevels of 10 to less than 30 ng/mL, and by 17% with levels of 30 ng/mL or more(P < .001). Even after adjusting for demographic and clinical characteristics, lower25(OH)D levels were independently associated with recent URTI (compared with25[OH]D levels of ≥30 ng/mL: odds ratio [OR], 1.36; 95% CI, 1.01-1.84 for <10 ng/mLand 1.24; 1.07-1.43 for 10 to <30 ng/mL). The association between 25(OH)D level andURTI seemed to be stronger in individuals with asthma and chronic obstructivepulmonary disease (OR, 5.67 and 2.26, respectively).Conclusions Serum 25(OH)D levels are inversely associated with recent URTI. Thisassociation may be stronger in those with respiratory tract diseases. Randomizedcontrolled trials are warranted to explore the effects of vitamin D supplementation onRTI.
Review The role of vitamin D in pulmonary disease: COPD, asthma, infection, and cancer Christian Herr1,3, Timm Greulich1, Rembert A Koczulla1, Silke Meyer2, Tetyana Zakharkina1,3, Meret Branscheidt1, Rebecca Eschmann1 and Robert Bals1,3* *Corresponding author: Robert Bals firstname.lastname@example.org Author Affiliations 1 Department of Internal Medicine, Division for Pulmonary Diseases, Philipps- Universtät Marburg, 35043 Marburg, Germany 2 Department of Internal Medicine, Division of Endocrinology & Diabetology, Department of Internal Medicine, University Hospital Marburg, 35043 Marburg, Germany 3 Department of Pulmonology, University of the Saarland, 66421 Homburg Saar, Germany For all author emails, please log on. Respiratory Research 2011, 12:31 doi:10.1186/1465-9921-12-31 Abstract The role of vitamin D (VitD) in calcium and bone homeostasis is well described. In the last years, it has been recognized that in addition to this classical function, VitD modulates a variety of processes and regulatory systems including host defense, inflammation, immunity, and repair. VitD deficiency appears to be frequent in industrialized countries. Especially patients with lung diseases have often low VitD serum levels. Epidemiological data indicate that low levels of serum VitD is associated with impaired pulmonary function, increased incidence of inflammatory, infectious or neoplastic diseases. Several lung diseases, all inflammatory in nature, may be related to activities of VitD including asthma, COPD and cancer. The exact mechanisms underlying these data are unknown, however, VitD appears to impact on the function of inflammatory and structural cells, including dendritic cells, lymphocytes, monocytes, and epithelial cells. This review summarizes the knowledge on the classical and newly discovered functions of VitD, the molecular and cellular mechanism of action and the available data on the relationship between lung disease and VitD status. Keywords: Vitamin D; mortality; asthma; COPD; respiratory tract infection; immunity Review VitD supplementation appears to be correlated with decreased total mortality . In the early 1920s a group of scientists independently discovered that irradiating of certain foods with ultraviolet light renders them antirachitic [2,3] and in 1922 Elmer V. McCollum identified an antirachitic substance in cod liver oil and called it "vitamin D" . While the role of VitD in calcium and bone homeostasis has been well described, its activities on other physiological and pathophysiological processes have been recognized only in the last years. Epidemiological data suggest that several lung diseases, all
inflammatory in nature, may be related to activities of VitD. VitD deficiency might have arole in the development of these diseases. The underlying mechanisms how VitDmetabolisms could be linked to the pathophysiology of these diseases are often complexand not fully understood. This review summarizes the role of VitD in lung diseases.Evolutionary aspectsVitD and its receptors are found throughout the animal kingdom and are often linked tobone and calcium metabolisms. The fact that precursors of VitD are found in ancientorganisms like krill and phytoplankton that existed unchanged for at least 750 millionyears  highlights its importance in physiologic and homeostatic processes.Variants of VitD and its receptors have been identified in higher terrestrial vertebrateslike humans, rodents , birds , amphibia , reptiles , as well as inzebrafish . These animals possess a calcified skeleton and depend on a functionalVitD hormone system for calcium and phosphorus homeostasis. Surprisingly, functionalVitD receptors (VDRs) have also been found in lampreys, an ancient vertebrate thatlacks a calcified skeleton . VDRs were also identified in animals with a naturallyimpoverished VitD status like the subterranean mole rat  and a frugivorousnocturnal mammal, the Egyptian fruit bat Cavaleros . VitD precursors have beenfound in ancient organisms like phytoplankton and zooplankton, some of which existunchanged for at least 750 million years [5,15]. Functional VitD hydroxylases have alsobeen characterized in bacteria like strains of actinomyces [16,17]and streptomyces [18,19]. The precursors of VitD in those organisms may function as anatural sunscreen to protect the host against UV-radiation, since the absorption spectraof pro-vitamin D and their photoproducts overlap with the absorption maxima of DNA,RNA, and proteins .Role of VitD in bone metabolismVitD, which is photosynthesized in the skin or has been derived from nutrition, ismetabolized two times, before it mediates its calcemic effects by binding to the nuclearVitD receptor (VDR) [21,22](Figure 1). The metabolizing enzymes belong to a group ofcytochrome P450 hydroxylases, which can be found in eukaryotes, bacteria, fungi andplants. In the human liver, the first hydroxylation of VitD on C-25 is performed bymitochondrial 25-hydroxylase enzymes (gene names: CYP27A1 and/orCYP2R1 ) that both belong to the cytochrome P450 family. The inactive 25-(OH)-vitamin D3 (25-(OH)D3) metabolite is further hydroxylated at position 1α by themitochondrial cytochrome P450 enzyme 25-hydroxyvitamin-D-1α-hydroxylase (genename: CYP27B1) and converted to the bioactive 1α,25-dihydroxyvitamin D(1,25-(OH)2D3). This latter step is mainly localized to the proximal kidney tubule ,however, many other cell types, including lung epithelial cells, are capable to performthis reaction [26-29]. The serum concentration of 25-(OH)D3 reflects the organisms VitDsupply . In the blood, VitD and the inactive, relatively stable 25-(OH)D3 metaboliteare bound in 99% to the vitamin D binding protein (DBP) . DBP polymorphisms (Gcphenotype) are related to the DBP concentration and VitD status . The 1α-hydroxylation of 25-(OH)D3 is upregulated by parathyroid hormone (PTH), calcitonin, lowcalcium- and phosphate levels as well as by estrogen, prolactin and growthhormone . Calcitonin, cortisol, high phosphate levels and 25-(OH)D3 suppress the
25-hydroxyvitamin D-1α-hydroxylase activity . 1,25-(OH)2D3 itself works as its ownnegative feedback regulator by induction of the expression of a 24-hydydroxylase(CYP24A1). Further, 1,25-(OH)2D3 decreases the production and secretion of PTH. PTHsynthesis and secretion is induced by decreased serum calcium levels, which aredetected by the calcium sensing receptor of the parathyroid gland. PTH effects renaltubular reabsorption of calcium, renal production of 1,25-(OH)2D3 and promotesosteoclastogenesis . Figure 1. Metabolism and effects of VitD. VitD can be obtained fromfood or from synthesis in the skin under exposure to light. The precursor is hydroxylatedcytochrome P450 25-hydroxylase enzymes CYP27A1 and/or CYP2R1 and subsequentlyby the cytochrome P450 enzyme 25-hydroxyvitamin D-1α-hydroxylase (CYP27B1) andconverted to the bioactive 1,25-(OH)2D3, which has role in Ca and bone metabolism and,in addition, in several other biological processes. Of note, bioactive 1,25-(OH)2D3 canalso be generated in lung epithelia cells and monocytes/macrophages.1,25-(OH)2D3 is essential for the development and maintenance of the growth plate,chondrocyte growth, and the mineralised bone . 1,25-(OH)2D3 modulates theosteoclastogenesis by regulation of the receptor activator of nuclear factor kappa B(RANK), RANK ligand (RANKL) and the soluble receptor osteoprotegerin (OPG) . Itincreases the expression of RANKL on the osteoblast surface, which supports maturationof progenitor and mature osteoclasts, and it inhibits OPG expression, which binds RANKLand prevents RANK mediated osteoclastogenesis .VitD deficiency causes the development of an imbalanced calcium- and phosphate-homeostasis and the occurrence of the bone diseases osteopenia, osteoporosis, rickets,and osteomalacia with a subsequently increased fracture risk . The 25-(OH)D3 serumconcentration is directly associated with bone mineral densitys. VitD deficiency hasseveral causes including inadequate sun exposure (and loss of functional capacity of theskin especially in the elderly), limited renal and hepatic function or insufficient intestinalresorption . In VitD deficiency, the feedback on the PTH gene promoter is lackingresulting in parathyroid hyperplasia, hyperparathyroidism, and a mineralization defect ofthe bone.1,25-(OH)2D3 regulates many target genes by binding to the VDR: approximately 3% ofthe mouse and human genome is regulated via the VitD pathway . As non-genomicaction of VitD in chondrocytes, it increases the membrane-lipid turnover, prostaglandinproduction and protease activity, leading to bone matrix modification and calcification.Additionally to the expression of VDR in bone and multiple tissues, the presence of 1α-hydroxylase in cells of several extrarenal tissues such as bone as well as skin, prostate,the respiratory and gastrointestinal tract, strongly suggest that VitD impacts onprocesses beyond the calcium and bone metabolism.Role of VitD in immunity and host defenseMore than a century ago (1849), the British physician C.J.B. Williams described the useof cod liver oil in the treatment of tuberculosis. He reported that among his tuberculosispatients, 206 out of 234 showed a "marked and unequivocal improvement" aftertreatment with cod liver oil . Since then manifold functions of VitD have been
discovered, indicating that VitD regulates many cellular processes and is potentiallyinvolved in the development of many diseases. Since the discovery of VDRs in a varietyof cells of the adaptive immune system such as B- and T-lymphocytes [42,43], therehave been numerous reports about the immunomodulatory activities of VitD.Cellular studies revealed that VitD modulates the activity of various defense and immunecells including monocytes, macrophages, lymphocytes, or epithelial cells:• Monocytes/macrophages: Low serum concentrations of VitD in patients with ricketscorrelate with decreased phagocytic activity of macrophages  that could be reversedby supplementation with 1,25-(OH)2D3 . Antimicrobial activity of macrophagesagainst M. tuberculosis is increased in the presence of 25-(OH)D3 after stimulation withmycobacterial ligands. Mycobacterial activation of toll-like receptor-2 (TLR-2) leads to anincreased expression of VDR and CYP27B that results in an increased conversion of 25-(OH)D3 to 1,25-(OH)2D3 and subsequent expression of the antimicrobial peptidecathelicidin via VDR [46,47].• B lymphocytes: It has been shown that 1,25-(OH)2D3 plays a role in B cell homeostasisby the inhibition of proliferation and induction of apoptosis of activated B cells .1,25-(OH)2D3inhibits the differentiation of B lymphocytes to plasma cells and memory Bcells. These mechanisms may contribute to the pathogenesis of B-lymphocyte relateddiseases like systemic lupus erythematosus (SLE). Patients with SLE have significantlower serum concentration of both 25-(OH)D3 and 1,25-(OH)2D3 [49,50].• T lymphocytes: A well-established function of VitD within the adaptive immune systemis its ability to modulate T lymphocyte proliferation and function. The biologically active1,25-(OH)2D3inhibits proliferation of TH lymphocytes  and shifts the expression ofcytokines from a TH1 based response towards a TH2 based profile [52,53]. Although1,25-(OH)2D3 might be able to involve direct effects on T lymphocytes through thesupport of differentiation of regulatory T cells, current data indicate that 1,25-(OH)2D3 exerts its influence on the adaptive immune response by modulating thefunctions of dendritic cells (DCs). Regulatory T cells seem to be activated by VitD withskewing of the Th1/Th2 balance towards Th2 . Of note, there is evidence for andagainst the role of VitD in Th2 biased diseases , which will be discussed in moredetail in the asthma section below.• Dendritic cells: The response of DCs to 1,25-(OH)2D3 is restricted to myeloic DC, thatexpress a different set of TLRs and cytokines than plasmacytoic DCs, which showed notolerogenic response to 1,25-(OH)2D3 . 1,25-(OH)2D3 inhibits the maturation of DCsand enhances the expression of cytokines like IL-10, thereby 1,25-(OH)2D3 inducestolerance through the suppression of T H1 lymphocyte development and the induction ofregulatory T cells .• Epithelial cells: Airway epithelial cell express enzymes of the VitD metabolism and arecapable to convert the precursor 25-(OH)D3 into the active 1,25-(OH)2D3 from [29,58].They are an important source of 1,25-(OH)2D3 that induces the expression of cathelicidinor CD14 by cells of the innate immune system. 1,25-(OH)2D3 converted by airwayepithelial cells is able to modulate the inflammatory profile after a viral infection byblocking the poly(I:C) induced chemokine and cytokine production while maintaining theantiviral activity [28,59]. As epithelial cells are primary targets of respiratory pathogensand cathelicidin has antibacterial and antiviral activity, a seasonal decrease of VitD-dependent epithelial host defense could contribute to increased numbers of lowerrespiratory tract infection (RTI) during winter.
Roles of VitD in pulmonary diseasesVitD has complex effects on pulmonary cell biology and immunity with impact oninflammation, host defense, wound healing, repair, and other processes. While theknowledge on direct mechanistic links between VitD and lung diseases is limited, anumber of epidemiological and experimental are available that highlight the relevance ofthis connection.a) AsthmaA connection between VitD status and asthma has been considered since many years.VitD deficiency has been blamed as one cause of increased asthma prevalence in the lastdecades. VDR variants were found to be associated with asthma in patientcohorts . A recent clinical investigation showed that high VitD levels are associatedwith better lung function, less airway hyperresponsiveness and improved glucocorticoidresponse . A population-based study suggested that lower VitD levels are associatedwith increased requirements for inhaled corticosteroids in children . Vitamin Dinsufficiency is common in this children with mild-to-moderate persistent asthma and isassociated with higher odds of severe exacerbation . Epidemiologic studies have alsoshown that maternal VitD intake during pregnancy protects from wheezing inchildhood [65,66]. In contrast, also data exist that children whose mothers had highVitD levels in pregnancy had an increased risk of eczema and asthma , suggestingthat the time point of Vit D supplementation seems to determine the susceptibility toatopic disease. On the experimental level in a murine asthma model, the VDR isnecessary for the development of an allergic airway inflammation .The underlying mechanisms how VitD modulates the pathogenesis of asthma are notclear. VitD may protect from developing respiratory infections that could serve as triggerfor a deterioration of asthma . VitD may also modulate the function of variousimmune cells as outlined above. Interestingly, application of VitD is potentially capableto overcome the poor glucocorticoid responsiveness in severe asthmatics byupregulation of IL-10 production from CD4+ T cells .b) Chronic obstructive lung disease (COPD)The connection between VitD status and COPD has attracted attention in the recentmonths. This is based on data from observational studies that determined levels of VitDin COPD patients. Black and colleagues examined data from the NHANES III data set(cross-sectional survey of 14091 adults in the US). After adjustment for potentialconfounders, a strong relationship between serum levels of VitD and lung function(FEV1 and FVC) was found . Although a significant correlation with airwayobstruction could not be found, the observed dose-response relationship may suggest acausal link . A number of studies have reported on 25-(OH)D3 levels in COPDpatients. Forli et al. found VitD deficiency (in this study defined as below 20 ng/ml) inmore than 50% of a cohort waiting for lung transplantation . In an outpatient studyon patients with COPD in Denmark, 68% of the participants had osteoporosis orosteopenia . A recent study showed that VitD deficiency is highly prevalent in COPDand correlates with variants in the VitD binding gene . There are several factors thatcould account for VitD deficiency in COPD patients: Poor diet, a reduced capacity ofaging skin for VitD synthesis, reduced outdoor activity and therefore sun exposure, anincreased catabolism by glucocorticoids, impaired activation because of renaldysfunction, and a lower storage capacity in muscles or fat due to wasting . Many
steps of the VitD pathway (intake, synthesis, storage, metabolism) can potentially bedisturbed in COPD patients.A single nucleotide polymorphism (SNP) of the DBP was shown to be associated with adecreased risk of COPD by a mechanism that is unclear . Similar SNPs in the genecoding for DBP may influence the level of circulating 25-(OH)D3 and 1,25-(OH)2D3 [32,78]. Therefore it has been hypothesized that their protective role might bemediated by the bioavailability of 1,25-(OH)2D3.The mechanisms that link VitD biology with the development of COPD are largelyspeculative:1) The association of VitD deficiency and reduced lung function could depend on thecalcemic effects of VitD. The vital capacity and total lung capacity was found to declinewith an increasing number of thoracic vertebral fractures as a direct consequence of VitDdeficiency . Nuti et al. observed 3030 ambulatory COPD patients and found a strongassociation between COPD severity and fractures . Kyphosis related to osteoporosiscaused limitation in rib mobility and inspiratory muscle function and correlated with areduction in FEV1 and FVC . The altered properties of the thoracic skeleton couldresult in failure of the respiratory muscles contributing to the pathophysiology of COPD.2) VitD deficiency could result in altered host defense of the lung with subsequentgrowth of an abnormal flora that triggers inflammation. Acute exacerbations of COPDare an important cause of hospitalization and lead to a faster decline in FEV 1 .Exacerbations are triggered by viruses, bacteria, atypical strains, or a combination ofthese [84-87]. Potential bacterial pathogens are detected in about 50% ofexacerbations. A therapeutic consequence would be the up-regulation of the innateimmune defense system. Wang and colleagues demonstrated that genes coding for theantimicrobial peptide cathelicidin (LL-37/hCAP-18) are regulated by VDRE-containingpromoters . In cultured monocytes, a local increase of the 1,25D3-VDR complexstimulates the production of LL-37, resulting in an improved intracellular eradicationofMycobacterium tuberculosis . The data demonstrated that the activation of TLRson human monocytes triggers a microbicidal pathway that is dependent on both theendogenous production and action of 1,25-(OH)2D3 through the VDR.3) The effect of VitD on extracellular matrix homeostasis not only in bone tissue, butalso within the lung may have a role in COPD development. Boyan et al. found VitD tobe an autocrine regulator of extracellular matrix turnover and growth factor release viamatrix metalloproteinases. Matrix metalloproteinasis-9 (MMP-9) has been shown tobe elevated in induced sputum of COPD patients and a causative role has beensuggested in the development of COPD . VitD also to attenuates TNF-alpha inducedupregulation of MMP-9 in keratinocytes . VitD deficiency may lead to a reducedattenuation of MMP-9 activity resulting in enhanced degradation of lung parenchyma.Recently, it has been recognized that COPD is a systemic disease  with severalclosely related comorbidities . Interestingly, VitD deficiency is associated with aequivalent spectrum of diseases including coronary heart disease, cancer, inflammatorydisease and infection . Comorbidities of COPD such as reduced bone mineral densityand skeletal muscle weakness[94,95] have been associated with low VitD serumconcentrations.
c) InfectionTuberculosisA number of candidate polymorphisms of VitD receptor (VDR) and VitD binding protein(DBP) have been identified that modulate the development of tuberculosis . Thegenotype tt (detected by Taq I digestion) is associated with decreased risk oftuberculosis. As described by Lewis et al., larger studies are required to determinewhether VDR polymorphisms play a role in genetic susceptibility to tuberculosisworldwide. In a recent meta-analysis, low serum levels of 25-(OH)D3were associatedwith a higher risk of active tuberculosis. The pooled effect size was 0.68 with 95% CI0.43 - 0.93. The authors concluded that the low VitD levels increase the risk of activetuberculosis . There are several randomized, double-blind, placebo-controlled trialsof VitD treatment in tuberculosis. In one study, 67 tuberculosis patients wererandomized to receive VitD (0.25 mg/day) or placebo during the 6 initial week of Tbtreatment . A statistical significant difference in sputum conversion (i.e, the changeof detectable to no detectable Mycobacteria in the sputum) was discovered in favor ofthe VitD group (100% vs. 76,7%; p = 0.002). Another trial was conducted in 192healthy adult tuberculosis contacts in London, United Kingdom . Participants wererandomized to receive a single oral dose of 2.5 mg VitD or placebo and followed up at 6weeks. VitD supplementation significantly enhanced the ability of participants wholeblood to restrict BCG-lux luminescence after 24 hours in vitro as compared with placebo,but did not affect antigen-stimulated IFN-gamma secretion after 96 hours. As the innateimmune responses are mobilized more rapidly than acquired immune responses, theauthors interpreted the 24- and 96-hour results as indicators of innate and acquiredresponses, respectively. They concluded that vitamin D supplementation may primarilyenhance innate responses to mycobacterial infection. Wejse et al. included 365tuberculosis patients starting anti-tuberculotic treatment in Guinea Bissau. 281patients completed the 12 month follow-up. The intervention was 100,000 IUcholecalciferol or placebo at inclusion and again at 5 and 8 months after start oftreatment. Reduction in TBscore and sputum smear conversion rates did not differamong VitD and placebo treated patients. Taken those data together there seems to bea benefit of VitD in the treatment of tuberculosis but this could not be reproduced in thelargest study so far.Respiratory tract infections (RTI)RTI are more common in the winter period than during summertime. Because the foodintake of VitD is insufficient, sunlight exposure is the primary determinant of VitD statusin humans, and seasonal differences in VitD level in human are well documented .During the winter months, there is insufficient UV-B exposure to produce sufficientamounts of VitD. Wintertime VitD insufficiency may explain seasonal variation ininfluenza and other, mostly viral, RTIs . Ginde et al. performed a secondaryanalysis of the Third National Health and Nutrition Examination Survey, hypothesizing anassociation between 25-(OH)D3 level and self-reported upper respiratory tract infections(URTI) in 18883 subjects . After adjusting for season, body mass index, smokinghistory, asthma, and COPD, lower 25-(OH)D3 levels were independently associated withrecent URTI. In patients with respiratory tract diseases (asthma and COPD) theassociation between 25-(OH)D3 level and URTI seemed to be even stronger (OR, 5.67and 2.26, respectively). Avenell and colleagues used data from the RECORD trial (VitD insecondary prevention of osteoporotic fractures; n = 5292) . In a "per protocol"analysis, a trend towards a benefit of VitD vs. placebo was detected, though not
statistically significant. Despite the large number of patients in these studies, restrictionsarise from the retrospective data analysis. A prospective cohort study included 800young Finnish men serving on a military base . Their serum 25-(OH)D3 wasmeasured in the beginning of a 6 month observational period. Subjects with low 25-(OH)D3 levels had significantly more days of absence from duty due to respiratoryinfection than did control subjects (p = 0.004). In a case control study a total of 150children (80 cases, 70 controls) was enrolled . Low serum 25-(OH)D3 (≤ 22.5nmol/l) was associated with a significantly higher odds ratio for having severe acutelower respiratory tract infections (p < 0.001). These studies support an role of VitD inthe development of lung infection.However, in a recent clinical trial, Li-Ng et al. randomized 162 adults to 50 μg VitD(2000 IU) daily or placebo for 12 weeks. Using a questionnaire they recorded theincidence and severity of upper RTI symptoms. Although VitD serum levels increasedsignificantly in the VitD treated group (vs. no change in the placebo group), there wasno benefit of VitD supplementation in decreasing the incidence or severity ofsymptomatic URTI . This may be explained by the relatively low number ofsubjects. Furthermore, the time period of 12 weeks was probably too short to show anyeffect. Taken together, there is growing evidence for a protective role of VitD in thedevelopment of RTI but high quality randomized clinical trials within a sufficiently highnumber of patients and for a sufficient period of time are missing. In a recentlypublished trial, the supplementation of 1500 E VitD per day resulted in deceasesincidence of influenza A by 64% .d) CancerA number of studies suggest that low levels of VitD are associated with an up to 50%increased risk of colon, prostate, or breast cancer [76,108]. As an example, a recentnested case-control study showed that pre-diagnostic levels of VitD are inverselycorrelated with the risk of colon cancer . For lung cancer, the picture is not clear atthe present time. While TaqI polymorphism of the VDR gene appears to be a risk factorfor lung cancer , low levels of VitD were only a cancer risk factor in subgroups, i.e.,in women and young individuals . In patients with diagnosed lung cancer, therewas no main effect of VitD level on overall survival. In preclinical animal modelsusing carcinogen (NNK)-induced lung carcinogenesis, application of 1,25-(OH)2D3 resulted in decreased cancer growth .ConclusionsVitD has a number of activities in addition to its effect on calcium and bone homeostasisand influences process such as immune regulation, host defense, inflammation, or cellproliferation. VitD deficiency is potentially involved in a number of lung disease. Severalhurdles must be overcome to validate the benefit of VitD-based therapies: 1) Basicmechanisms are not clear and the involved molecular pathways are likely difficult toidentify because VitD impacts on a variety of biological processes in parallel. 2)Conclusive data from interventional studies are missing for many disease entities. 3)Since VitD has been used for many years, the pharmaceutical industry might hesitate instarting a development program. Nevertheless, the data available indicate that VitDcould be beneficial for the prevention or therapy of important lung diseases.
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