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Tuberculosis and Vitamin D What Is the Evidence for Interaction?

a review by

Christian 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 emergency

production of singlet oxygen through radiation of porphyrins has been

by the World Health Organzation (WHO). New solutions are needed in

suggested as a plausible explanation of why Finsens therapy worked.16 The

many areas, such as adjunctive treatments and improved quality of

authors also suggest that possible effects of UV radiation on the immune

care,2 preferably with a simple approach that is feasible in low-income

reactions in the skin and granuloma may lie behind the success of the

countries.3 Vitamin D has been declared a possible adjuvant therapy;4

treatment, i.e. a vitamin-D-mediated reaction.

this article presents a review of the available literature on vitamin D and

TB interaction.

Vitamin D Used in Treatment

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

Vitamin D deficiency (VDD) has been proposed as one of the

was recognised that the effect of cod liver oil on rickets was because of the

aetiological factors for TB, and the effect of vitamin D on the cell-

rich vitamin D content. Using this knowledge, attempts were made to use

mediated immune response is of vital importance in conquering TB.

calciferol in TB treatment. This was first described in 1943 by Charpy and

This hypothesis was proposed in modern times by Davies in 1985 based

later by Dowling.17,18 There are numerous reports of a very convincing effect

on observations of a high TB prevalence among Asian immigrants in

of treatment of lupus vulgaris with calciferol or its precursor, ergosterol.1924

London who had low vitamin D levels. However, this was not a new

The largest population treated was 1,230 patients with various forms of skin

hypothesis in the medical community.

TB: 748 patients had lupus vulgaris and of these 38.4% were completely

Historical Aspects

UV radiation on lupus vulgaris could be attributed to the skin formation of

cured.25 A Dutch group found that the well-documented effect of Finsens

vitamin D, and even noted more rapid improvements when Finsens lamps
Cod Liver Oil

and ergosterol were used together in the treatment.15

Vitamin D has been used in various forms both before and after the advent
of the antibiotic era. Cod liver oil, which is rich in vitamin D, was first

Various forms of vitamin D were also used successfully in scrofula20 and

recommended for TB in 1766 by Darbey, and throughout the 18th

abdominal TB,26,27 and with varying results in pulmonary TB.2831 In the

century cod liver oil was widely used to treat consumption.7 Bennett

literature the use of vitamin D for pulmonary TB was heavily debated,3234 as

initiated cod liver oil treatment at his TB sanatorium in Edinburgh, with

well as the appropriate dosage. Charpy initially used 1,200,000IU per week

good results: Cod liver oil has like no other remedy rapidly restored the

but later reduced the dosage to 600,000IU per 60kg bodyweight every fifth

exhaustive powers of the patient, improved the nutritive functions

day for lupus vulgaris.6,17 Most authors followed this regime, and Marcussen

generally, stopped or diminished emaciation, checked the perspiration,

even noted more relapses when using less than 100,000IU per day.35 One

quieted the cough and expectoration, and produced the most favourable

group found that 30,000IU/day was sufficient for treating pulmonary TB.36

influence on the local disease. From the Hospital for Consumption and

Current recommendations are not to exceed 50,000IU/day to avoid

Diseases of the Chest in London it was reported that one to two

toxicity,37 but some data show that 100,000IU/day may also be acceptable

tablespoons of cod liver oil two to four times daily arrested disease in

for a limited period of time,38 although only trials using 10,000IU/day for

18%, improved disease in 63% and had no effect in 19%.9 A 19%

longer periods have not reported toxicity.39 Interestingly, the dosage of cod

reduction in deaths due to consumption in Philadelphia between 1847

liver oil previously mentioned would be equivalent to 6,000-24,000IU/day.37

and 1852 was attributed to the widespread use of cod liver oil
treatment.10 However, it gradually became clear that although it was a

Safety in terms of effect on calcium concentration, blood pressure and

useful adjunctive therapy at a time when few other remedies were

electrocardiogram was found to be satisfactory,32,40 but there were

available, it was not a cure-all for TB, which was also noted by those

frequent cases of intoxication27,41,42 and concerns about provoking

advocating cod liver oil.

10,11

Light on Mycobacteria
In 1903, Niels Finsen was awarded the Nobel Prize for his discovery of the
usefulness of light therapy for lupus vulgaris.12 The theoretical background
was believed to be a specific ultraviolet (UV)-induced bacteria killing.13,14
However, in 1958 vitamin D was also considered as the mechanism of effect
of light therapy on lupus; it was shown that the UV radiation in Finsen lamps

Christian Wejse is a Senior Registrar in the Department of

Infectious Diseases at Aarhus University Hospital. His research
interests centre on tuberculosis and HIV in low-resource
settings, and pneumonia. He is the author or co-author of 11
publications in international peer-reviewed journals, including
the Journal of Infectious Diseases, the Pediatric Infectious
Disease Journal and Epidemiology, and a referee for Thorax
and the Journal of Infectious Disease. Dr Wejse received his
MD and PhD from the University of Aarhus.

could yield 100IU vitamin D per square centimetre, enough to equalise the
obtained skin concentration after an oral dose of 500,000IU.15 Recently,

TOUCH BRIEFINGS 2008

E: wejse@dadlnet.dk

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exacerbations.23,43,44 After streptomycin and isoniazid began to be

1,25(OH)2D3 analogues for immunosuppressive purposes in, for

widely used, some still recommended 600,000IU calciferol twice a

instance, autoimmune diseases.54,55 To the knowledge of the author,

week as supplementary treatment,45 in particular in cases with

there are no studies available regarding the effect of the host immune

streptomycin resistance.43

response in TB patients treated with the dosage commonly used for VDD,
let alone the supraphysiological dosage of vitamin D that was common

Ever since lymphoid cells were

less than 50 years ago.

discovered to richly express the

Specific Evidence from In Vitro Studies Linking

vitamin D receptor, there has been a

Tuberculosis and Vitamin D

growing understanding of the overall

vitamin D and host defence against MTB. 1,25(OH)2D3 has repeatedly

importance of vitamin D in various

been shown to enhance macrophage phagocytosis of live MTB.5663 The

aspects of the immune system.

There are, however, a number of laboratory studies that specifically link

mechanism is possibly a 1,25(OH)2D3-induced increased nitric oxide (NO)

synthesis, leading to suppression of MTB or Mycobacterium bovis in
macrophages.62,64,65 A major part of the available 1,25(OH)2D3 seems to

Marcussen from the Finsen Institute reported that 83.5% of 280 lupus

stem from local production: Cadranel has shown that lymphocytes

vulgaris patients treated with vitamin D2 alone were clinically and

isolated with bronchoalveolar lavage from 14 TB patients did in fact

histologically symptom-free during the course, but there were frequent

produce 1,25(OH)2D3, while this was not seen in controls.66 This may

relapses and only 33% remained symptom-free after five years of follow-

be a result of increased 1-hydroxylase activity. The enzyme can also be

up.35 This observation led them to conclude that vitamin D acted on the host

found in extrarenal tissue, such as skin and lymphnodes, and expression is

rather than on the tubercle bacillus.

increased in granulomatous diseases67,68 and upregulated by toll-like

receptor (TLR) stimulation.63

Immunological Aspects
When the local environment is rich in 1,25(OH)2D3 there are other effects
More Than a Calcium-metabolism-regulating Hormone

besides NO release. Rook et al. have shown that monocytes cultured in the

Ever since lymphoid cells were discovered to richly express the vitamin D

presence of 1,25(OH)2D3 have an increased capacity of MTB-triggered

receptor (VDR),46 there has been a growing understanding of the overall

tumour necrosis factor (TNF)- release,69 and Stabel et al. showed that

importance of vitamin D in various aspects of the immune system.47,48

1,25(OH)2D3 increased cytokine secretion in splenocytes from mice

Vitamin D modulates the proliferation, differentiation and immune

infected with M. paratuberculosis.70

function of lymphocytes and monocytes. The VDR is found in significant

49

concentrations in the T lymphocyte and macrophage populations.

Tuberculosis Immunopathology in Relation to

However, its highest concentration is in the immature immune cells of the

Vitamin-D-mediated Immunology

thymus and the mature CD8 T lymphocytes.50 CD4+ T cells express VDRs

Recently, we have come closer to an understanding of the specific role

at a lower level,48 but have been shown to increase five-fold following

of vitamin D in immune reactions towards infection with MTB.63 In a

activation.51 Microarray technology has identified over 102 targets of

series of elegant experiments published in Science in 2006, Liu et al.

1,25 di-hydroxy-cholecalciferol (1,25(OH)2D3) in CD4+ T cells. Of these

showed that TLR 1 and 2 stimulation of human macrophages results in:

102 genes, 57 were downregulated and 45 were upregulated by

reduced viability of intracellular MTB in human monocytes and

1,25(OH)2D3 treatment of the CD4+ T cells.51

macrophages but not in dendritic cells; upregulation of the VDR gene

in monocytes; and hydroxylation of 25(OH)D3 into 1,25(OH)2D3. They

Intriguingly, it seems that 1,25(OH)2D3 is capable of stimulating immune

further showed that adding 1,25(OH)2D3 to human monocytes led to

responses in certain circumstances and suppressing them in others.49 Griffin

upregulation of cathelicidin, an antimicrobial peptide, and a reduction

sums up the current evidence in the following statements:52

of viable MTB in infected macrophages; in fact, simultaneous addition

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

the current evidence implicates 1,25(OH)2D3 in the enhancement of

localised innate immune responses;
the evidence points to a significant role for 1,25(OH)2D3 in the negative
regulation of Th1-type immunity; and
administration of 1,25(OH)2D3 agonists is associated with the
promotion of Th2 or Treg-type T cells.
Looking at vitamin-D-mediated immunological reactions with TB in mind,

There has been some hesitation to

supplement tuberculosis patients with
vitamin D for fear of hypercalcaemia.

we may interpret this as beneficial in terms of strengthening the innate

response that is vital to host defence, and a limitation of unsuitably
strong Th1 reactions may also be desirable. However, it must be
emphasised that the immune response to mycobacterium tuberculosis

authors called for clinical trials of the inexpensive vitamin D

(MTB) is complex and multifaceted and not completely understood,53 and

supplementation towards infectious diseases. A recent trial by

evaluating the impact of interventions on host immune defences can be

Martineau et al.71 did in fact test vitamin D for TB contacts, and found

difficult. Current research mainly focuses on treating VDD or using

that vitamin D significantly enhanced the ability of whole blood to

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Tuberculosis and Vitamin D What Is the Evidence for Interaction?

restrict bacillus Calmette Guerin (BCG)-lux luminescence in vitro,

no association with single-nucleotide polymorphisms (SNPs), but did

indicating that vitamin D supplementation primarily enhances innate

show an association with TB in a family-based analysis at the haplotype

responses to mycobacterial infection.

level.83 We have confirmed this finding in a case-control study.84 A group

from Peru was even able to show a difference in treatment response to

Epidemiological Aspects

TB depending on the genotype of the patient.85 However, a recent metaanalysis has concluded that the studies so far have been underpowered

Vitamin D Status Among Patients with

and that the results are inconclusive.86 Later, Soeborg et al. published a

Active Tuberculosis Infection

large study from a highly TB-endemic region and showed no association

Clinical studies are few and with small populations. Davies found lower

with FokI, TaqI and ApaI loci;87 therefore, it is not likely that VDR

25(OH)D3 concentrations in TB patients but similar 1,25(OH)2D3

polymorphisms play a major role in TB susceptibility.

concentrations among 50 TB patients and controls in London.72 These

findings were repeated in 15 East African TB patients and 15 controls.73

Intervention Studies Supplementing Tuberculosis

Grange found in 40 Indonesian patients a less extensive disease in TB

Patients with Vitamin D

patients with high vitamin D levels, but found similar 25(OH)D3

Two randomised studies have been reported. One study from Egypt

concentrations.74 Olmos reported significantly lower 25(OH)D3 and

included 24 children of whom 12 were given vitamin D 1,000IU/day for

1,25(OH)2D3 in 21 TB patients compared with 42 healthy controls.75 A

two months. The treated patients had a better clinical outcome with

Chinese study found no difference in 25(OH)D3 or 1,25(OH)2D3 among

respect to weight, fever, lymph nodes and cough, but not thoracic

24 TB patients and controls,76 whereas an Indian study reported

X-ray.88 Another study from Indonesia gave vitamin D 10,000IU/day or

significantly lower 25(OH)D3 concentrations in 35 TB patients than in 16

placebo to 67 pulmonary TB patients for the first six weeks of

controls.77 A report from Wilkinson on Gujarati Asians in London found

treatment and reported sputum conversion in 100% of those receiving

significantly lower 25(OH)D3 levels among 91 TB patients than in 116

vitamin D compared with only 77% of those receiving placebo.

healthy contacts, with an odds ratio (OR) of 2.9 for VDD being associated
with TB.78 The same group has also reported a very high frequency (76%)

There has been some hesitation to supplement TB patients with vitamin

of VDD among 210 consecutive TB patients, mainly foreign-born.79

D for fear of hypercalcaemia. Hypercalcaemia in TB has been described

Recently, this observation was supported by an Australian study that

mostly in case histories in which other conditions may also have played

demonstrated lower geometric mean vitamin D levels in immigrants with

a role.89 In one case, low-dosage vitamin supplementation may have

latent TB infection than in those with no M. tuberculosis infection, as well

been to blame.90 However, hypercalcaemia has also been described in

as lower vitamin D levels in immigrants with TB or past TB than in those

larger series: in 27.5% of intrathoracic TB patients in Nigeria, and in

with latent TB infection.

25% of TB patients in both Greece and Sweden.91,92 However,

hypercalcaemia was reported to be very rare among TB patients in

The largest observational study on the subject matter was conducted in

Hong Kong, Malaysia and Turkey.9395 In one of the studies in which

a high-burden setting in Africa, where we found an association

vitamin D was given to TB patients, no case of hypercalcaemia was

between TB and vitamin D insufficiency, but intriguingly no association

found in either those supplemented with vitamin D or those not

with severe vitamin D insufficiency.80 Furthermore, the observation that

supplemented.96 Also noteworthy are older reports of high-dose

African-Americans are more susceptible to infection with MTB81 and

therapy in which calcium was monitored carefully and hypercalcaemia

also more frequently suffer from VDD82 has been interpreted as a VDD-

not seen. An Indian study from 1957 used 600,000IU/week in eight

induced susceptibility towards TB. The above-mentioned observations

pulmonary and 19 extra-pulmonary TB cases with resulting

are frequently cited and, taken together, they point towards TB

improvement in clinical status, and they reported that hypercalcemia

patients having increased frequency of VDD; they may also suggest that

was absent in all.30

this VDD was implicated when the patient acquired MTB or developed
active disease. However, there are no prospective studies available in

Conclusion

which patients with VDD are followed for risk of latent or active TB.

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

vitamin D point towards a causal relationship. However, despite

Genetic Polymorphisms in the Vitamin D Receptor and

advances in the knowledge of the potent immunomodulatory

Susceptibility to Tuberculosis

activity of vitamin D, its role in TB disease progression is still unknown,

Certain VDR polymorphisms have been associated with higher risk of

largely because no prospective studies or major randomised trials have

TB.78 A study including TB cases and controls from Guinea Bissau showed

been reported.

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