tuberculosis and vitamin d

8/9/2019 Tuberculosis and Vitamin D

1/4

Bacterial Infections

a review by

Chris t ian Wejse

Senior Registrar, Department of Infectious Diseases, Aarhus University Hospital, and Senior Research Fellow, Bandim Health Project, Guinea Bissau

The epidemic of tuberculosis (TB) has been declared a global emergencyby the World Health Organzation (WHO). 1 New solutions are needed inmany areas, such as adjunctive treatments and improved quality ofcare, 2 preferably with a simple approach that is feasible in low-incomecountries. 3 Vitamin D has been declared a possible adjuvant therapy; 4

this article presents a review of the available literature on vitamin D andTB interaction.

Vitamin D deficiency (VDD) has been proposed as one of theaetiological factors for TB, and the effect of vitamin D on the cell-mediated immune response is of vital importance in conquering TB.This hypothesis was proposed in modern times by Davies in 1985 basedon observations of a high TB prevalence among Asian immigrants inLondon who had low vitamin D levels. 5 However, this was not a newhypothesis in the medical community.

Historical Aspects

Cod Liver Oil

Vitamin D has been used in various forms both before and after the adventof the antibiotic era. Cod liver oil, which is rich in vitamin D, was firstrecommended for TB in 1766 by Darbey, 6 and throughout the 18thcentury cod liver oil was widely used to treat consumption. 7 Bennettinitiated cod liver oil treatment at his TB sanatorium in Edinburgh, withgood results: Cod liver oil has like no other remedy rapidly restored theexhaustive powers of the patient, improved the nutritive functionsgenerally, stopped or diminished emaciation, checked the perspiration,quieted the cough and expectoration, and produced the most favourableinfluence on the local disease. 8 From the Hospital for Consumption andDiseases of the Chest in London it was reported that one to twotablespoons of cod liver oil two to four times daily arrested disease in

18%, improved disease in 63% and had no effect in 19%. 9 A 19%reduction in deaths due to consumption in Philadelphia between 1847and 1852 was attributed to the widespread use of cod liver oiltreatment. 10 However, it gradually became clear that although it was auseful adjunctive therapy at a time when few other remedies wereavailable, it was not a cure-all for TB, which was also noted by thoseadvocating cod liver oil. 10,11

Light on MycobacteriaIn 1903, Niels Finsen was awarded the Nobel Prize for his discovery of theusefulness of light therapy for lupus vulgaris. 12 The theoretical backgroundwas believed to be a specific ultraviolet (UV)-induced bacteria killing. 13,14

However, in 1958 vitamin D was also considered as the mechanism of effectof light therapy on lupus; it was shown that the UV radiation in Finsen lampscould yield 100IU vitamin D per square centimetre, enough to equalise theobtained skin concentration after an oral dose of 500,000IU. 15 Recently,

production of singlet oxygen through radiation of porphyrins has beensuggested as a plausible explanation of why Finsens therapy worked. 16 Theauthors also suggest that possible effects of UV radiation on the immunereactions in the skin and granuloma may lie behind the success of thetreatment, i.e. a vitamin-D-mediated reaction.

Vitamin D Used in Treatment

Cod liver oil remained an important part of TB treatment as late as 1960.7

Itwas recognised that the effect of cod liver oil on rickets was because of therich vitamin D content. Using this knowledge, attempts were made to usecalciferol in TB treatment. This was first described in 1943 by Charpy andlater by Dowling. 17,18 There are numerous reports of a very convincing effectof treatment of lupus vulgaris with calciferol or its precursor, ergosterol. 1924

The largest population treated was 1,230 patients with various forms of skinTB: 748 patients had lupus vulgaris and of these 38.4% were completelycured. 25 A Dutch group found that the well-documented effect of FinsensUV radiation on lupus vulgaris could be attributed to the skin formation ofvitamin D, and even noted more rapid improvements when Finsens lampsand ergosterol were used together in the treatment. 15

Various forms of vitamin D were also used successfully in scrofula 20 andabdominal TB, 26,27 and with varying results in pulmonary TB. 2831 In theliterature the use of vitamin D for pulmonary TB was heavily debated, 3234 aswell as the appropriate dosage. Charpy initially used 1,200,000IU per weekbut later reduced the dosage to 600,000IU per 60kg bodyweight every fifthday for lupus vulgaris. 6,17 Most authors followed this regime, and Marcusseneven noted more relapses when using less than 100,000IU per day. 35 Onegroup found that 30,000IU/day was sufficient for treating pulmonary TB. 36

Current recommendations are not to exceed 50,000IU/day to avoidtoxicity,37 but some data show that 100,000IU/day may also be acceptablefor a limited period of time, 38 although only trials using 10,000IU/day for

longer periods have not reported toxicity. 39 Interestingly, the dosage of codliver oil previously mentioned would be equivalent to 6,000-24,000IU/day. 37

Safety in terms of effect on calcium concentration, blood pressure andelectrocardiogram was found to be satisfactory, 32,40 but there werefrequent cases of intoxication 27,41,42 and concerns about provoking

Tuberculosis and Vitamin D What Is the Evidence for Interaction?

Christian Wejse is a Senior Registrar in the Department ofInfectious Diseases at Aarhus University Hospital. His researchinterests centre on tuberculosis and HIV in low-resourcesettings, and pneumonia. He is the author or co-author of 11publications in international peer-reviewed journals, includingthe Jou rna l o f Inf ec tio us Dis eases, the Pediatric Infectious

Disease Journal and Epidemiology , and a referee forThorax and the Jou rnal of In fec tio us Di sease. Dr Wejse received hisMD and PhD from the University of Aarhus.

E: [email protected]

107 T O U C H B R I E F I N G S 2 0 0 8


2/4


exacerbations. 23,43,44 After streptomycin and isoniazid began to bewidely used, some still recommended 600,000IU calciferol twice aweek as supplementary treatment, 45 in particular in cases withstreptomycin resistance. 43

Marcussen from the Finsen Institute reported that 83.5% of 280 lupusvulgaris patients treated with vitamin D 2 alone were clinically andhistologically symptom-free during the course, but there were frequent

relapses and only 33% remained symptom-free after five years of follow-up. 35 This observation led them to conclude that vitamin D acted on the hostrather than on the tubercle bacillus.

Immunological Aspects

More Than a Calcium-metabolism-regulating HormoneEver since lymphoid cells were discovered to richly express the vitamin Dreceptor (VDR),46 there has been a growing understanding of the overallimportance of vitamin D in various aspects of the immune system. 47,48

Vitamin D modulates the proliferation, differentiation and immunefunction of lymphocytes and monocytes. 49 The VDR is found in significant

concentrations in the T lymphocyte and macrophage populations.However, its highest concentration is in the immature immune cells of thethymus and the mature CD8 T lymphocytes. 50 CD4+ T cells express VDRsat a lower level, 48 but have been shown to increase five-fold followingactivation. 51 Microarray technology has identified over 102 targets of1,25 di-hydroxy-cholecalciferol (1,25(OH)2D3) in CD4 + T cells. Of these102 genes, 57 were downregulated and 45 were upregulated by1,25(OH)2D3 treatment of the CD4 + T cells.51

Intriguingly, it seems that 1,25(OH)2D3 is capable of stimulating immuneresponses in certain circumstances and suppressing them in others. 49 Griffinsums up the current evidence in the following statements: 52

the current evidence implicates 1,25(OH)2D3 in the enhancement oflocalised innate immune responses;

the evidence points to a significant role for 1,25(OH)2D3 in the negativeregulation of Th1-type immunity; and

administration of 1,25(OH)2D3 agonists is associated with thepromotion of Th2 or Treg-type T cells.

Looking at vitamin-D-mediated immunological reactions with TB in mind,we may interpret this as beneficial in terms of strengthening the innateresponse that is vital to host defence, and a limitation of unsuitablystrong Th1 reactions may also be desirable. However, it must be

emphasised that the immune response to mycobacterium tuberculosis(MTB) is complex and multifaceted and not completely understood, 53 andevaluating the impact of interventions on host immune defences can bedifficult. Current research mainly focuses on treating VDD or using

1,25(OH)2D3 analogues for immunosuppressive purposes in, forinstance, autoimmune diseases. 54,55 To the knowledge of the author,there are no studies available regarding the effect of the host immuneresponse in TB patients treated with the dosage commonly used for VDD,let alone the supraphysiological dosage of vitamin D that was commonless than 50 years ago.

Specific Evidence from In Vitro Studies LinkingTuberculosis and Vitamin DThere are, however, a number of laboratory studies that specifically linkvitamin D and host defence against MTB. 1,25(OH)2D3 has repeatedlybeen shown to enhance macrophage phagocytosis of live MTB. 5663 Themechanism is possibly a 1,25(OH)2D3-induced increased nitric oxide (NO)synthesis, leading to suppression of MTB or Mycobacterium bovis inmacrophages. 62,64,65 A major part of the available 1,25(OH)2D3 seems tostem from local production: Cadranel has shown that lymphocytesisolated with bronchoalveolar lavage from 14 TB patients did in factproduce 1,25(OH)2D3, while this was not seen in controls. 66 This may

be a result of increased 1

-hydroxylase activity. The enzyme can also befound in extrarenal tissue, such as skin and lymphnodes, and expression isincreased in granulomatous diseases 67,68 and upregulated by toll-likereceptor (TLR) stimulation. 63

When the local environment is rich in 1,25(OH)2D3 there are other effectsbesides NO release. Rook et al. have shown that monocytes cultured in thepresence of 1,25(OH)2D3 have an increased capacity of MTB-triggeredtumour necrosis factor (TNF)- release, 69 and Stabel et al. showed that1,25(OH)2D3 increased cytokine secretion in splenocytes from miceinfected with M. paratuberculosis .70

Tuberculosis Immunopathology in Relation toVitamin-D-mediated Immunology Recently, we have come closer to an understanding of the specific roleof vitamin D in immune reactions towards infection with MTB. 63 In aseries of elegant experiments published in Science in 2006, Liu et al.showed that TLR 1 and 2 stimulation of human macrophages results in:reduced viability of intracellular MTB in human monocytes andmacrophages but not in dendritic cells; upregulation of the VDR genein monocytes; and hydroxylation of 25(OH)D3 into 1,25(OH)2D3. Theyfurther showed that adding 1,25(OH)2D3 to human monocytes led toupregulation of cathelicidin, an antimicrobial peptide, and a reductionof viable MTB in infected macrophages; in fact, simultaneous addition

of 25(OH)D3 and TLR 2/1-ligand also upregulated cathelicidin. The

authors called for clinical trials of the inexpensive vitamin Dsupplementation towards infectious diseases. A recent trial byMartineau et al. 71 did in fact test vitamin D for TB contacts, and foundthat vitamin D significantly enhanced the ability of whole blood to

108 E U R O P E A N I N F E C T I O U S D I S E A S E

Ever since lymphoid cells were

discovered to richly express the

vitamin D receptor, there has been a

growing understanding of the overall

importance of vitamin D in various

aspects of the immune system.

There has been some hesitation to

supplement tuberculosis patients with

vitamin D for fear of hypercalcaemia.


3/4

Tuberculosis and Vitamin D What Is the Evidence for Interaction?

restrict bacillus Calmette Guerin (BCG)- lux luminescence in vitro ,indicating that vitamin D supplementation primarily enhances innateresponses to mycobacterial infection.

Epidemiological Aspects

Vitamin D Status Among Patients with Active Tuberculos is In fect ionClinical studies are few and with small populations. Davies found lower25(OH)D3 concentrations in TB patients but similar 1,25(OH)2D3concentrations among 50 TB patients and controls in London. 72 Thesefindings were repeated in 15 East African TB patients and 15 controls. 73

Grange found in 40 Indonesian patients a less extensive disease in TBpatients with high vitamin D levels, but found similar 25(OH)D3concentrations. 74 Olmos reported significantly lower 25(OH)D3 and1,25(OH)2D3 in 21 TB patients compared with 42 healthy controls. 75 AChinese study found no difference in 25(OH)D3 or 1,25(OH)2D3 among24 TB patients and controls, 76 whereas an Indian study reported

significantly lower 25(OH)D3 concentrations in 35 TB patients than in 16controls. 77 A report from Wilkinson on Gujarati Asians in London foundsignificantly lower 25(OH)D3 levels among 91 TB patients than in 116healthy contacts, with an odds ratio (OR) of 2.9 for VDD being associatedwith TB.78 The same group has also reported a very high frequency (76%)of VDD among 210 consecutive TB patients, mainly foreign-born. 79

Recently, this observation was supported by an Australian study thatdemonstrated lower geometric mean vitamin D levels in immigrants withlatent TB infection than in those with no M. tuberculosis infection, as wellas lower vitamin D levels in immigrants with TB or past TB than in thosewith latent TB infection.

The largest observational study on the subject matter was conducted ina high-burden setting in Africa, where we found an associationbetween TB and vitamin D insufficiency, but intriguingly no associationwith severe vitamin D insufficiency. 80 Furthermore, the observation thatAfrican-Americans are more susceptible to infection with MTB 81 andalso more frequently suffer from VDD 82 has been interpreted as a VDD-induced susceptibility towards TB. The above-mentioned observationsare frequently cited and, taken together, they point towards TBpatients having increased frequency of VDD; they may also suggest thatthis VDD was implicated when the patient acquired MTB or developedactive disease. However, there are no prospective studies available inwhich patients with VDD are followed for risk of latent or active TB.

Genetic Polymorphisms in the Vitamin D Receptor and Susceptibility to TuberculosisCertain VDR polymorphisms have been associated with higher risk ofTB.78 A study including TB cases and controls from Guinea Bissau showed

no association with single-nucleotide polymorphisms (SNPs), but didshow an association with TB in a family-based analysis at the haplotypelevel.83 We have confirmed this finding in a case-control study. 84 A groupfrom Peru was even able to show a difference in treatment response toTB depending on the genotype of the patient. 85 However, a recent meta-analysis has concluded that the studies so far have been underpoweredand that the results are inconclusive. 86 Later, Soeborg et al. published alarge study from a highly TB-endemic region and showed no associationwith FokI, TaqI and ApaI loci; 87 therefore, it is not likely that VDRpolymorphisms play a major role in TB susceptibility.

Intervention Studies Supplementing TuberculosisPatients with Vitamin DTwo randomised studies have been reported. One study from Egyptincluded 24 children of whom 12 were given vitamin D 1,000IU/day fortwo months. The treated patients had a better clinical outcome withrespect to weight, fever, lymph nodes and cough, but not thoracicX-ray.88 Another study from Indonesia gave vitamin D 10,000IU/day or

placebo to 67 pulmonary TB patients for the first six weeks oftreatment and reported sputum conversion in 100% of those receivingvitamin D compared with only 77% of those receiving placebo.

There has been some hesitation to supplement TB patients with vitaminD for fear of hypercalcaemia. Hypercalcaemia in TB has been describedmostly in case histories in which other conditions may also have playeda role. 89 In one case, low-dosage vitamin supplementation may havebeen to blame. 90 However, hypercalcaemia has also been described inlarger series: in 27.5% of intrathoracic TB patients in Nigeria, and in25% of TB patients in both Greece and Sweden. 91,92 However,hypercalcaemia was reported to be very rare among TB patients in

Hong Kong, Malaysia and Turkey.9395

In one of the studies in whichvitamin D was given to TB patients, no case of hypercalcaemia wasfound in either those supplemented with vitamin D or those notsupplemented. 96 Also noteworthy are older reports of high-dosetherapy in which calcium was monitored carefully and hypercalcaemianot seen. An Indian study from 1957 used 600,000IU/week in eightpulmonary and 19 extra-pulmonary TB cases with resultingimprovement in clinical status, and they reported that hypercalcemiawas absent in all. 30

ConclusionIn conclusion, the highlighted aspects of our knowledge of TB and

vitamin D point towards a causal relationship. However, despiteadvances in the knowledge of the potent immunomodulatoryactivity of vitamin D, its role in TB disease progression is still unknown,largely because no prospective studies or major randomised trials havebeen reported.

1. Rook GA, Dheda K, Zumla A, Immune responses to tuberculosisin developing countries: implications for new vaccines,Nat Rev Immunol , 2005;5(8):6617.

2. Harries AD, Hargreaves NJ, Kemp J, et al., Deaths fromtuberculosis in sub-Saharan African countries with a highprevalence of HIV-1,Lancet , 2001;357(9267):151923.

3. Enarson DA. Foreword. In: Davies PDO (ed.),Clinical Tuberculosis. 3rd ed , London: Arnold, 2003;xiv.

4. Zasloff M, Fighting infections with vitamin D,Nat Med ,2006;12(4):38890.

5 Davies PD, Church HA, Brown RC, Woodhead JS, Raised serumcalcium in tuberculosis patients in Africa,Eur J Respir Dis,1987;71(5):3414.

6. Holtz F, Frohberg H, Role of the calcinosis factor (vitamin D,dihydrotachysterin) in therapy of tuberculosis,Beitr Klin Tuberk Spezif Tuberkuloseforsch, 1957;117(2):26575.

7. Grad R, Cod and the consumptive: a brief history of cod-liver oilin the treatment of pulmonary tuberculosis,Pharm Hist ,2004;46(3):10620.

8. Bennett JH,Treatise on the Oleum Jecoris Aselli , London:S Highley, 1841.

9. Still A, Therapeutics and Materia Medica,London Monthly Journ al , 1849;239.

10. Wood GB, A Trea tis e on the Pra ct ice of Medic ine , 4th ed .,Philladelphia: Lippincott, Grambo and Co., 1855;967.

11. Rodriguez B, Sethi AK, Cheruvu VK, et al., Predictive value of

plasma HIV RNA level on rate of CD4 T-cell decline in untreatedHIV infection, JAM A, 2006;296(12):14981506.

12. Lyngbye J, Lyssagen,Niels Finsen og hans team pFinsensinstituttet, 1st ed., Copenhagen: Gyldendal, 2003.

13. David HL, Jones WD Jr, Newman CM, Ultraviolet lightinactivation and photoreactivation in the mycobacteria,Infect Immun, 1971;4(3):31819.

14. Riley RL, Knight M, Middlebrook G, Ultraviolet susceptibility ofBCG and virulent tubercle bacilli, Am Rev Resp ir Dis,1976;113(4):41318.

15. van der Lugt L, Rottier PB, Finsen therapy and vitamin D, Ac taDerm Venereol , 1958;38(4):26473.

16. Moller KI, Kongshoj B, Philipsen PA, et al., How Finsens light

109E U R O P E A N I N F E C T I O U S D I S E A S E


4/4

cured lupus vulgaris,Photodermatol Photoimmunol Photomed ,2005;21(3):11824.

17. Charpy J, Aspects of vitamin and functional substance therapyin dermatology,Bull Med , 1950;64(24):5559.

18. Dowling GB, Prosser Thomas EW, Treatment of lupus vulgariswith calciferol,Lancet , 1946;1:91922.

19. Riehl, Two years experience with vitamin D2 in the treatmentof tuberculosis of the skin, Arc h Kl in Exp Derma tol , 1950;191:61518.

20. Ruiter M, Groen HD, The effect of nonirradiated ergosterol incalciferol-treated tuberculosis cutis,Dermatologica,1949;99(6):34552.

21. Gutierrez PD, Fernandez MC, Vitamin D2 in cutaneoustuberculosis; (progress report), Ac ta Med Ph ili pp, 1950;7(1):559.

22. Thaler E, Treatment of tuberculosis of the skin with massivedoses of vitamin D2,Med Monatsschr , 1950;4(6):4524.

23. Macrae DE The use of calciferol in tuberculous conditions,Lancet , 1947;249(6439):1357.

24. Lomholt S, Calciferol therapy of lupus vulgaris, Ac ta DermVenereol , 1950;30(4):32933.

25. Pogorzelski J, Miedzinski F, Six years of calciferol therapy intuberculosis of the skin,Dermatologica, 1954;109(6):35569.

26. Ellman P, Anderson K, Calciferol in Tuberculosis Peritonitiswith Disseminated Tuberculosis,BMJ , 1948;1:394.

27. Wallis HR, Tuberculous mesenteric adenitis in children,Br Med J , 1955;1(4906):12833.28. Gerecke W, Vitamin D2 alone and in combination with TB

1/698 in the treatment of pulmonary tuberculosis, Z Tu be rk ,1950;95(34):1827.

29. Brincourt J, Liquefying effect on suppurations of an oral doseof calciferol,Presse Med , 1969;77(13):46770.

30. Ghosh PK, Vitamin D2 in tuberculosis, J India n Med Asso c ,1957;29(3):9093.

31. Trautwein H, Stein E, Vitamin D2 and pulmonary tuberculosis;effects and therapeutic results,Beitr Klin Tuberk Spezif Tuberkuloseforsch, 1952;107(4):295313.

32. Gertler W, The question of late injuries in long lasting vitaminD treatment of cutaneous tuberculosis, Z Tube rk ,1953;103(13):2650.

33. Kalkoff KW, Chemotherapy and vitamin D therapy of skintuberculosis,Ergeb Gesamten Tuberkuloseforsch, 1956;13:33170.

34. Winterberg H, Vigantol therapy in early tuberculous infectionsof the lungs, and in exsudative pulmonary tuberculosis, Z Tube rk , 1950;95(34):14650.

35. Marcussen PV, Treatment of lupus vulgaris with calciferolalone; results after five years of observation,Dan Med Bull ,1955;2(5):12936.

36. Seeber F, The use of vitamin D2 in the treatment of pulmonarytuberculosis, Z Tube rk , 1950;95(3-4):1515.

37. Holick MF, Resurrection of vitamin D deficiency and rickets, J C lin Invest , 2006;116(8):206272.

38. Vieth R, Vitamin D supplementation, 25-hydroxyvitamin Dconcentrations, and safety, Am J Cl in Nu tr , 1999;69(5):84256.

39. Hathcock JN, Shao A, Vieth R, Heaney R, Risk assessment forvitamin D, Am J C lin Nu tr , 2007;85(1):618.

40. Fruhwald R, Changes in the blood analysis in vitamin D2treatment of cutaneous tuberculosis,Dtsch Gesundheitsw ,1953;8(3):679.

41. Sonne LM, Calciferol in dermatology,Ugeskr Laeger ,1952;114(4):10913.

42. Dowling GB, The present status of vitamin D2 in the treatmentof lupus vulgaris,Dermatologica, 1957;115(4):4915.

43. Fielding J, Maloney JJ, Calciferol, streptomycin, and para-aminosalicylic acid in pulmonary tuberculosis,Lancet ,1951;2(14):61417.

44. Jongmans LJ, Hopmans PJ, Kars HJ, Michgelsen H, Danger ofreactivating tuberculous processes in the lungs with theadministration of massive doses of vitamin D2,Ned Tijdschr Geneeskd , 1950;94(34):247073.

45. Grassi A, Modern therapy of cutaneous tuberculosis,MinervaMed , 1957;48(51):226973.

46. Provvedini DM, Tsoukas CD, Deftos LJ, Manolagas SC, 1,25-dihydroxyvitamin D3 receptors in human leukocytes,Science,1983;221(4616):11813.

47. Veldman CM, Cantorna MT, DeLuca HF, Expression of 1,25-dihydroxyvitamin D(3) receptor in the immune system, ArchBiochem Biophys, 2000;374(2):3348.

48. Hayes CE, Nashold FE, Spach KM, Pedersen LB, Theimmunological functions of the vitamin D endocrine system,Cell Mol Biol (Noisy-Le-Grand), 2003;49(2):277300.

49. Manolagas SC, Hustmyer FG, Yu XP, 1,25-Dihydroxyvitamin D3and the immune system,Proc Soc Exp Biol Med , 1989;191(3):23845.

50. Deluca HF, Cantorna MT, Vitamin D: its role and uses inimmunology,FASEB J , 2001;15(14):257985.

51. Mahon BD, Wittke A, Weaver V, Cantorna MT, The targets of

vitamin D depend on the differentiation and activation statusof CD4 positive T cells, J Ce ll Biochem, 2003;89(5):92232.

52. Gauzzi MC, Purificato C, Donato K, et al. Suppressive effect of1alpha,25-dihydroxyvitamin D3 on type I IFN-mediatedmonocyte differentiation into dendritic cells: impairment offunctional activities and chemotaxis, J Imm unol , 2005;174(1):27076.

53. Raja A Immunology of tuberculosis,Indian J Med Res,2004;120(4):21332.

54. Cantorna MT, Zhu Y, Froicu M, Wittke A, Vitamin D status,1,25-dihydroxyvitamin D3, and the immune system, Am J Cl inNutr , 2004;80(Suppl. 6):1717S20S.

55. Daniel C, Schlauch T, Zugel U, et al., 22-ene-25-oxa-vitamin D:a new vitamin D analogue with profound immunosuppressivecapacities,Eur J Clin Invest , 2005;35(5):3439.

56. Crowle AJ, Ross EJ, May MH, Inhibition by 1,25(OH)2-vitamin

D3 of the multiplication of virulent tubercle bacilli in culturedhuman macrophages,Infect Immun, 1987;55(12):294550.57. Crowle AJ, Salfinger M, May MH, 1,25(OH)2-vitamin D3

synergizes with pyrazinamide to kill tubercle bacilli incultured human macrophages, Am Rev Resp ir Dis, 1989;39(2):54952.

58. Crowle AJ, Ross EJ, Comparative abilities of variousmetabolites of vitamin D to protect cultured humanmacrophages against tubercle bacilli, J Leukoc Biol ,1990;47(6):54550.

59. Crowle AJ, May MH, Inhibition of tubercle bacilli in culturedhuman macrophages by chloroquine used alone and incombination with streptomycin, isoniazid, pyrazinamide, andtwo metabolites of vitamin D3, An tim ic rob Agen ts Chemothe r ,1990;34(11):221722.

60. Denis M, Killing ofMycobacterium tuberculosiswithin humanmonocytes: activation by cytokines and calcitriol,Clin ExpImmunol , 1991;84(2):2006.

61. Chandra G, Selvaraj P, Jawahar MS, et al., Effect of VitaminD(3) on Phagocytic Potential of Macrophages with LiveMycobacterium tuberculosisand Lymphoproliferative Responsein Pulmonary Tuberculosis, J C lin Imm unol , 2004;24(3):24957.

62. Rockett KA, Brookes R, Udalova I, et al., 1,25-Dihydroxyvitamin D3 induces nitric oxide synthase andsuppresses growth ofMycobacterium tuberculosisin a humanmacrophage-like cell line,Infect Immun, 1998;66(11):531421.

63. Liu PT, Stenger S, Li H, et al., Toll-like receptor triggering of avitamin D-mediated human antimicrobial response,Science,2006;311(5768):177073.

64. Waters WR, Nonnecke BJ, Rahner TE, et al., Modulation ofMycobacterium bovis-specific responses of bovine peripheral

blood mononuclear cells by 1,25-dihydroxyvitamin D(3),ClinDiagn Lab Immunol , 2001;8(6):120412.65. Waters WR, Palmer MV, Nonnecke BJ, et al.,Mycobacterium

bovisinfection of vitamin D-deficient NOS2-/- mice,MicrobPathog, 2004;36(1):1117.

66. Cadranel JL, Garabedian M, Milleron B, et al., Vitamin Dmetabolism by alveolar immune cells in tuberculosis:correlation with calcium metabolism and clinicalmanifestations,Eur Respir J , 1994;7(6):110310.

67. Zehnder D, Bland R, Williams MC, et al., Extrarenal expressionof 25-hydroxyvitamin d(3)-1 alpha-hydroxylase, J C linEndocrinol Metab, 2001;86(2):88894.

68. Sharma OP, Hypercalcemia in granulomatous disorders: aclinical review,Curr Opin Pulm Med , 2000;6(5):4427.

69. Rook GA, Taverne J, Leveton C, Steele J, The role of gamma-interferon, vitamin D3 metabolites and tumour necrosis factorin the pathogenesis of tuberculosis,Immunology , 1987;62(2):22934.

70. Stabel JR, Goff JP, Influence of vitamin D3 infusion and dietarycalcium on secretion of interleukin 1, interleukin 6, and tumornecrosis factor in mice infected withMycobacterium pa rat ub erc ulos is, Am J Ve t Res, 1996;57(6):8259.

71. Martineau AR, Wilkinson RJ, Wilkinson KA, et al. A SingleDose of Vitamin D Enhances Immunity to Mycobacteria, Am J Respir Crit Care Med , 2007;176(2):20813.

72. Davies PD, Brown RC, Woodhead JS, Serum concentrations ofvitamin D metabolites in untreated tuberculosis,Thorax ,1985;40(3):18790.

73. Davies PD, Church HA, Brown RC, Woodhead JS, Raised serumcalcium in tuberculosis patients in Africa,Eur J Respir Dis,1987;71(5):3414.

74. Grange JM, Davies PD, Brown RC, et al., A study of vitamin Dlevels in Indonesian patients with untreated pulmonarytuberculosis,Tubercle, 1985;66(3):18791.

75. Olmos JM, Martinez J, Riancho JA, et al., Phosphocalciummetabolism disorders in patients with active pulmonarytuberculosis,Med Clin (Barc), 1991;96(3):924.

76. Chan TY, Poon P, Pang J, et al., A study of calcium andvitamin D metabolism in Chinese patients with pulmonarytuberculosis, J Trop Med Hyg, 1994;97(1):2630.

77. Sasidharan PK, Rajeev E, Vijayakumari V, Tuberculosis andvitamin D deficiency, J Assoc Phys ici ans Ind ia, 2002;50:5548.

78. Wilkinson RJ, Llewelyn M, Toossi Z, et al., Influence of vitaminD deficiency and vitamin D receptor polymorphisms ontuberculosis among Gujarati Asians in west London: a case-control study,Lancet , 2000;355(9204):61821.

79. Ustianowski A, Shaffer R, Collin S, et al., Prevalence andassociations of vitamin D deficiency in foreign-born personswith tuberculosis in London, J In fec t , 2005;50(5):4327.

80. Wejse C, Olesen R, Rabna P, et al., Serum 25-hydroxy-vitaminD in a West African population of tuberculosis patients andun-matched healthy controls, Am J Cli n Nu tr , 2007;86(5):137683.

81. Stead WW, Senner JW, Reddick WT, Lofgren JP, Racialdifferences in susceptibility to infection byMycobacteriumtuberculosis, N Engl J Med , 1990;322(7):4227.

82. Harris SS, Vitamin D and African Americans, J Nu tr ,2006;136(4):11269.

83. Bornman L, Campbell SJ, Fielding K, et al., Vitamin D receptorpolymorphisms and susceptibility to tuberculosis in WestAfrica: a case-control and family study, J Inf ec t Dis,2004;190(9):163141.

84. Olesen R, Wejse C, Velez DR, et al., DC-SIGN (CD209),pentraxin 3 and vitamin D receptor gene variants associatewith pulmonary tuberculosis risk in West Africans,GenesImmun, 2007;8(6):45667.

85. Roth DE, Soto G, Arenas F, et al., Association between vitaminD receptor gene polymorphisms and response to treatment ofpulmonary tuberculosis, J In fec t D is, 2004;190(5):92027.

86. Lewis SJ, Baker I, Davey SG, Meta-analysis of vitamin Dreceptor polymorphisms and pulmonary tuberculosis risk,Int J Tuberc Lung Dis, 2005;9(10):11747.

87. Soborg C, Andersen AB, Range N, et al., Influence ofcandidate susceptibility genes on tuberculosis in a highendemic region,Mol Immunol , 2007;44(9):221320. Epub2006 Dec 6.

88. Morcos MM, Gabr AA, Samuel S, et al., Vitamin Dadministration to tuberculous children and its value,Boll ChimFarm, 1998;137(5):15764.

89. awn SD, Macallan DC, Hypercalcemia: a manifestation ofimmune reconstitution complicating tuberculosis in an HIV-infected person,Clin Infect Dis, 2004;38(1):1545.

90. Bradley GW, Sterling GM, Hypercalcaemia and hypokalaemiain tuberculosis,Thorax 1978;33(4):4647.

91. Lind L, Ljunghall S, Hypercalcemia in pulmonary tuberculosis,Ups J Med Sci , 1990;95(2):15760.

92. Roussos A, Lagogianni I, Gonis A,et al., Hypercalcaemia inGreek patients with tuberculosis before the initiation of anti-tuberculosis treatment,Respir Med , 2001;95(3):18790.

93. Chan TY, Symptomatic hypercalcaemia is rare in tuberculouspatients in Hong Kong, Ann Trop Med Pa ras ito l , 1996;90(6):6634.

94. Tan TT, Lee BC, Khalid BA, Low incidence of hypercalcaemia intuberculosis in Malaysia, J T rop Med Hyg, 1993;96(6):34951.

95. Kelestimur F, Guven M, Ozesmi M, Pasaoglu H, Doestuberculosis really cause hypercalcemia?, J Endo cri no l Inv es t ,1996;19(10):67881.

96. Fuss M, Karmali R, Pepersack T, et al., Are tuberculouspatients at a great risk from hypercalcemia?,Q J Med ,1988;69(259):86978.


E U R O P E A N I N F E C T I O U S D I S E A S E110

tuberculosis and vitamin d

Documents