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Vitamin D As An Adjuvant Therapy For Tuberculosis Pharmacogenomic Implications
Vitamin D As An Adjuvant Therapy For Tuberculosis Pharmacogenomic Implications
Vitamin D As An Adjuvant Therapy For Tuberculosis Pharmacogenomic Implications
1
Specialist Registrar, Liverpool Heart & Chest Epidemiological link between TB & vitamin D deficiency
Hospital NHS Foundation Trust, Liverpool, UK Vitamin D in high doses was used to treat TB prior to the availability of anti
2
Regional Tuberculosis Centre, Liverpool Heart biotics and subsequently moved to the back burner. In 1961, it was observed that
& Chest Hospital NHS Foundation Trust, Pakistani immigrants in Glasgow had widespread rickets and osteomalacia secondary
Thomas Drive, Liverpool L14 3PE, UK
†
Author for correspondence:
Tel.: +44 151 228 1616 Keywords: genetic subgroups • immigrants • screening • supplementation • vitamin D
E-mail: p.d.o.davies@liv.ac.uk
to vitamin D deficiency that was not related to dietary 2.5 mg vitamin D3 in patients receiving intensive-phase
deficiency and it was suggested that advice on the proph- treatment for smear positive pulmonary TB, did not sig-
ylaxis of vitamin D deficiency should be given to all nificantly affect time to sputum culture conversion in the
Pakistanis and Indians in the UK [2] . There is growing study population [14] .
evidence that vitamin D and mycobacterial infection These differences in outcomes could be due to a vari-
are closely linked and that patients with TB have lower ety of factors, explained well by Awumey and colleagues,
levels of vitamin D than those without [3] . that the intrinsic hydroxylase activity in some Asians
Immigrants in London, from the Indian subconti- may be higher compared with non-Asian controls and
nent, on a purely vegetarian diet were found to have the possible effect of rifampicin and isoniazid on vita-
an 8.5-fold increased risk of TB, compared with those min D metabolism, exacerbating the above effect [15] . In
who ate meat and fish daily. This increased risk is pos- addition, there is the possibility of a paradoxical reaction,
tulated to have been caused by deficiencies in possibly in which more severe disease leads to the paradoxical
iron, vitamin B12 or vitamin D [4] . depletion of vitamin D metabolism during treatment.
There is evidence of an inverse relationship between
serum vitamin D levels and the likelihood of both hav- “...with an increasing incidence of MDR-
ing any mycobacterial TB infection and the likelihood of and XDR-TB, its associated mortality and the
having TB/past TB rather than latent TB infection [5] , a decreased effectiveness of routine anti-TB drugs,
concept first suggested by the corresponding author, over where does treatment with vitamin D
25 years ago, by demonstrating lower levels of vitamin D find a place?”
in patients with TB when compared with matched con-
trols [6] . A case–control study by Wilkinson in Gujurati The current drugs in TB treatment are so powerful,
Indians residing in northwest London, demonstrated that that vitamin D supplementation can add very little.
vitamin D deficiency was significantly associated with That brings us to resistance patterns in TB. MDR-TB
active TB disease and those with undetectable serum is caused by resistance to the two most powerful first-
vitamin D levels, carried the greatest risk of TB [7] . Racial line anti-TB drugs – isoniazid and rifampicin. XDR-TB
differences in the pathogenesis of TB have been suggested is caused by resistance to isoniazid and rifampicin, in
to be due to a decline in vitamin D levels, that may cor- addition to any fluoroquinolone and at least one of three
relate with a decline in cell-mediated immunity, in a injectable second-line drugs. The exact scale of the prob-
person infected with the tuberculosis bacillus, resulting lem of MDR- and XDR-TB is not known and there
in marked differences in rates of TB infection between has been limited reduction in drug-resistance patterns
black and white patients, one study reporting rates among making it increasingly difficult to contain the disease.
racial/ethnic minorities were five- to ten-times higher However, with an increasing incidence of MDR- and
than those in white patients [8] . It is postulated, that a XDR-TB, its associated mortality and the decreased
decrease in the exposure to sunlight when a person moves effectiveness of routine anti-TB drugs, where does treat-
from a country with plentiful sunlight to one with less ment with vitamin D find a place? There is limited
sunlight with a decline in vitamin D [9] , may have an knowledge of the factors influencing the development
important role to play and is supported by the pattern of of these resistance patterns and there may be a place for
increased rates of TB during the winter season [10] . a trial of vitamin D in MDR- or XDR-TB to determine
if augmentation of current treatment will be effective.
Disappointing trials of therapy
There have been no randomized control trials looking Prevention with vitamin D supplementation may
at the supplementation of vitamin D in the prevention be more valuable
of TB. Martineau et al. demonstrated that a single dose Could the dose of vitamin D have an effect on the out-
of vitamin D enhanced the ability of an individual come? The treatment of severe vitamin D deficiency
who had contact with TB to restrict mycobacterial bio could be ample to reduce the risk of TB. Vitamin D
luminescence at 24 h post-inoculation ex vivo [11] . In a deficiency, brought about by immigration from tropi-
randomized study of 365 adults in Guinea-Bissau after cal to temperate climates and from an area of abundant
the administration of three doses (at initiation of treat- sunlight to that of less, appears to be a risk factor for
ment, months 5 and 8) no effect was seen on the primary TB. The mean serum vitamin D concentration has
outcome (a specially developed TB score) [12] . been shown to drop fourfold or more, on emigration
Another trial has shown that adding vitamin D to the from Asia to Britain [16] . The implication for vitamin D
treatment of TB makes no difference to the outcome [13] . therapy is that it should be given to individuals, prob-
Moreover, a recent multicenter randomized controlled ably lifelong, as they move from a tropical to a tem-
trial has shown that the administration of four doses of perate climate, to prevent the development of TB in
9 Davies PDO, Nisar M. Racial differences of non-western immigrants: a randomized 17 Bellamy R, Ruwende C, Corrah T et al.
Mycobacterium tuberculosis infection. N. Eng. clinical trial. Osteoporos. Int. 22(3), 873–882 Tuberculosis and chronic hepatitis B virus
J. Med. 322, 1672 (1990). (2011). infection in Africans and variation in the
10 Nagayama N, Ohmori M. Seasonality in 14 Martineau AR et al. High-dose vitamin D3 vitamin D receptor gene. J. Infect. Dis.
various forms of tuberculosis. Int. J. Tuberc. during intensive-phase antimicrobial 179(3), 721–724 (1999).
Lung Dis. 10, 1117–1122 (2006). treatment of pulmonary tuberculosis: 18 Papiha SS, Agarwal SS, White I. Association
11 Martineau AR, Wilkinson RJ, Wilkinson KA, a double-blind randomised controlled trial. between phosphoglucomutase (PGM1) and
Newton SM, Kampmann B, Hall BM. A Lancet 377(9761), 242–250 (2011). group-specific component (Gc) subtypes and
single dose of vitamin D enhances immunity 15 Awumey EM, Mitra DA, Hollis BW, tuberculosis. J. Med. Genet. 20(3), 220–222
to mycobacteria. Am. J. Respir. Crit. Care Kumar R, Bell NH. Vitamin D metabolism is (1983).
Med. 176(2), 208–213 (2007). altered in Asian Indians in the southern United 19 Martineau AR, Leandro AC, Anderson ST
12 Wejse C, Gomes VF, Rabna P et al. States: a clinical research center study. J. Clin. et al. Association between Gc genotype and
Vitamin D as supplementary treatment for Endocrinol. Metab. 83(1), 169–173 (1998). susceptibility to TB is dependent on vitamin D
tuberculosis: a double-blind, randomized, 16 Henderson JB, Dunnigan MG, status. Eur. Respir. J. 35(5), 1106–1112 (2010).
placebo-controlled trial. Am. J. Respir. Crit. McIntosh WB, Abdul-Motaal AA, Hole D. 20 Wejse C, Gomes FV, Rabna P et al.
Care Med. 179(9), 843–850 (2009). Asian osteomalacia is determined by dietary Vitamin D as supplementary treatment for
13 Wicherts IS, Boeke AJ, van der Meer IM et al. factors when exposure to ultra-violet radiation tuberculosis: a double-blind randomized
Sunlight exposure or vitamin D is restricted-a risk factor model. Q J. Med. placebo-controlled trial. Am. J. Respir. Crit.
supplementation for vitamin D-deficient 281, 923–933 (1990). Care Med. 179, 843–850 (2009).