Vitamin D and tuberculosis

Before antimycobacterial medicines were introduced (around 1950), the best support for patients with tuberculosis (TB) appeared to be sunshine. For TB patients who needed bed rest, sun-facing balconies in sanatoria were considered to be more therapeutic than the usual dark hospital wards. In 1904, William Osler noted that rabbits inoculated with tubercle bacilli succumbed rapidly if kept in the dark, but not in the open air. He advised patients treated at home to have as many hours as possible in the sunshine. Cod liver oil was also used — a large controlled trial at the Brompton Hospital, London in 1848 showed clear benefit of cod liver oil in treating pulmonary consumption.1

However, sunlight is our major source of vitamin D and cod liver oil is rich in vitamin D3 (5 g oil provides 10 μg, the recommended daily intake for most adults). So can vitamin D help prevent or treat TB?

In the past 15 years, there has been a surge of research interest in whether vitamin D can be a protective influence in a range of diseases — notably, type 1 diabetes, multiple sclerosis, colorectal cancer, psoriasis and TB.2

The vitamin D receptor has been found in many different types of cells, including T and B lymphocytes, monocytes and macrophages, and respiratory epithelial cells. Most of these cells also express the enzyme that can make the active 1,25-dihydroxyvitamin D internally. In cell culture, macrophages exposed to vitamin D produce antimicrobial activity against intracellular Mycobacterium tuberculosis by induction of the peptide cathelicidin LL-37.3

In this issue of the Journal, MacLachlan and Cowie suggest that the seasonal incidence of TB in Australia (highest in October to December) is partly determined by differences in ultraviolet radiation exposure and subsequent vitamin D synthesis.4 In south-eastern Australia, serum 25-hydroxyvitamin D (25-OHD) levels are at their lowest in September.5 In Cape Town, at the same latitude as Sydney (33°S), TB notifications peak at the same time of the year, about 2 months after the lowest annual measured levels of 25-OHD. In the northern hemisphere, TB notifications peak in the United Kingdom at the opposite time of the year (March to May) and also in late spring (in reverse to the incidence times for other respiratory diseases). MacLachlan and Cowie report that TB notifications in Australia show a stronger seasonal pattern in the southern states.4 In contrast, in the United States, Willis and colleagues, although noting a seasonal pattern in new cases of TB, did not find an association between latitude and new TB cases (ie, TB notifications were not higher in the northern states compared with the southern states).6

A case–control study found that isoniazid and rifampicin reduced serum 25-OHD levels in patients with TB.7 To exclude this possible drug effect, Nnoaham and Clarke reviewed studies in which culture-positive TB patients had not yet started antimycobacterial treatment and found that in six of seven studies, patients had significantly lower 25-OHD levels.8 Talat and colleagues noted that in a cohort of household contacts of TB patients, those with low 25-OHD levels had a greatly increased risk of progression to active TB; however, this was only a small prospective study.9

Randomised controlled trials of vitamin D need to be carried out alongside antibacterial medications and the possibility of coexistent HIV infection. A trial in Guinea-Bissau did not show benefit;10 however, the trial may have used vitamin D doses that were too low to be effective. In a large UK trial,11 time to reach negative sputum culture averaged 36 days with vitamin D and 43.5 days with antimycobacterial agents alone (not significant). When analysed by genotypes of vitamin D receptor, adding vitamin D significantly hastened sputum culture conversion in patients with the TT genotype (only 10% of all patients). Based on the same trial, with additional data, among the 76% of the original patients who fulfilled criteria for per-protocol analysis, vitamin D was found to accelerate sputum smear conversion in all vitamin D receptor genotypes and, from differences in haematology and cytokines, appeared to enhance the anti-TB therapy.12

To summarise, available evidence suggests that low vitamin D levels increase the risk of reactivation of TB. However, there is relatively little evidence to support a clinically meaningful therapeutic effect alongside present anti-TB chemotherapy.