Review
Vitamin D and solar ultraviolet radiation in the risk and treatment of tuberculosis

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Summary

Improved understanding of the association between tuberculosis and vitamin D is needed to inform clinical practice. Vitamin D has both immunostimulatory and immunosuppressive effects relevant to human antimycobacterial responses. Ultraviolet radiation, the main source of vitamin D, also induces immunomodulation and could affect the relation between vitamin D and tuberculosis. Clinical trials of vitamin D supplementation in patients with tuberculosis have produced largely negative results, prompting the review of dosing regimens—an explanation for low 25-hydroxyvitamin D status in patients with active tuberculosis is also needed. The reporting of vitamin D deficiency needs to address assay inaccuracies, rising thresholds to define sufficiency, and scarce knowledge of the concentrations needed for optimum immune responses. Future research to measure the effect of the inflammatory setting on serum concentrations of 25-hydroxyvitamin D, at tuberculosis diagnosis and during recovery, could help to account for 25-hydroxyvitamin D changes in these concentrations in patients with tuberculosis. Studies into the role of vitamin D supplementation in latent tuberculosis justify clinical trials in this population, but pose methodological challenges. Vitamin D trials in patients with active tuberculosis should be done in well selected populations using adequate vitamin D doses, although such doses remain undefined.

Introduction

Tuberculosis is the second most common cause of death from infection worldwide.1 Vitamin D deficiency is prevalent across broad geographical boundaries;2, 3, 4, 5 an association between the two could be of major relevance to world health.

Mycobacterium tuberculosis is a human pathogen with efficient transmission and immune evasion strategies.6, 7 After the HIV pandemic, tuberculosis re-emerged as a global emergency,8 peaking in 2006 to more than 9 million cases annually, then falling to an estimated 8·8 million by 2010.1 The Stop TB Partnership has an ambitious goal to eliminate tuberculosis by 2050 (to less than one case per 1 million every year).9 Traditionally classified as either latent or active disease, the outcome of infection with M tuberculosis is now perceived as a continuum.10, 11 For clarity, in this Review we refer to latent tuberculosis infection and active tuberculosis. Prevention, diagnosis, and management of both active tuberculosis and latent infection remain challenging, despite substantial improvements in diagnostic tests,12, 13 new drugs for active tuberculosis,14, 15, 16 and new regimens for latent infection.17

Drawbacks with tuberculosis treatment regimens, particularly rising drug resistance and HIV–tuberculosis co-infection, are driving the need for novel treatment approaches. Strategies to accelerate recovery and reduce treatment durations include the development of new antimicrobial agents and the investigation of adjunctive immunotherapies; both are priority areas of tuberculosis research.18 Mechanisms of action of potential adjunctive treatments include promotion of T-helper-1 (Th1) antimycobacterial immune responses (eg, administration of interferon gamma),19 upregulation of host innate (ie, macrophage) antimycobacterial immune responses (eg, vitamin D and nitric oxide),20 decrease of immunopathology mediated tissue damage because of excessive inflammatory responses (eg, corticosteroids),21 and alteration of the metabolic state of tuberculosis bacilli to shift them out of a non-replicative, antibiotic-resistant state (eg, tumour necrosis factor α [TNFα] inhibitors).22 There has been much hope that vitamin D might fulfil at least some of these actions as a potential adjunctive treatment in active or latent tuberculosis.

Vitamin D is derived from endogenous synthesis after exposure of the skin to solar ultraviolet radiation. Receptors for its active form, 1,25-dihydroxyvitamin D, are widely expressed in human cells, including monocytes and macrophages, dendritic, T cells, B cells, and natural killer cells.23 The effects of 1,25-dihydroxyvitamin D are immunostimulatory in monocytes and macrophages and immunosuppressive in dendritic and T cells. Ultraviolet radiation causes immune changes too, mainly downregulatory, in antigens encountered close to the time of the exposure.24, 25

Basic science,26, 27 clinical research,28, 29, 30 population studies,31 and historical treatment practices (eg, phototherapy and cod-liver oil)32, 33 suggest that inexpensive, accessible vitamin D could play an important part in the treatment of tuberculosis. Sufficiency in vitamin D has been hypothesised to decrease the risk of infection with tuberculosis after exposure,34 limits the progression from latent to active tuberculosis,35 and, as an adjunct to antimicrobial treatment, decreases the duration and improves the effectiveness of treatment.20, 28, 30

Questions about the relation between tuberculosis, vitamin D, and ultraviolet radiation are largely unexplored. These include reconciliation of contradictory immunological actions of 1,25-dihydroxyvitamin D related to the balance between innate immunity (antimicrobial peptides and macrophages in particular) and adaptive immunity, understanding of the immunological effects of exposure to ultraviolet radiation (a potentially important confounder of the vitamin D–tuberculosis relation), and consideration of alternative hypotheses that explain the common finding of low vitamin D status in patients with active tuberculosis. We reviewed the scientific literature to provide evidence, explore contradictions, and suggest alternative hypotheses.

Section snippets

Background

When 7-dehydrocholesterol in the plasma membrane of human keratinocytes is exposed to ultraviolet B (UVB) radiation, it is converted to previtamin D3, followed by a thermal reaction to form vitamin D3 (cholecalciferol). Some foods contain vitamin D3 or vitamin D2, which is synthesised by plants after UVB irradiation; however, these only contribute small amounts of the total vitamin D requirements in most individuals. The physiological effects of D2 and D3 are interchangeable, although oral

Ultraviolet radiation-induced immunological effects and tuberculosis

Ultraviolet radiation is the major source of vitamin D and its immunological effects should therefore be assessed alongside those of vitamin D.94 Exposure of animals and human beings to ultraviolet light results in downregulation of T and B-cell response to various antigens, including tumour antigens, contact sensitisers, microorganisms, and alloantigens.25 Immunomodulation pathways vary depending on the antigen; the spectrum, dose and frequency of radiation exposure, time between exposure and

Historical perspective

In the 19th century, cod-liver oil was used in Europe to prevent childhood diseases such as rickets and tuberculosis.33, 108 Although not a cure, a benefit in patients with tuberculosis was weight gain.108 It was sometimes given in large doses (0·5–1·0 pint every 4–8 days or one or two tablespoons two to four times daily). The chemical structures of the vitamins D were discovered by Windaus and colleagues109 in the 1930s and the antirachitic component of cod-liver oil, identified in rats, was

Clinical trials of vitamin D supplementation

Although observational studies justify trials of vitamin D supplementation to inhibit progression from latent to active tuberculosis, such studies pose difficulties because they need large numbers of patients, long follow-up, and would need to show a clear additional benefit over evidence-based treatments for latent infection (eg, isoniazid preventive treatment and antiretroviral therapy for patients with HIV). Of note, vitamin D supplementation does not decrease the risk of tuberculosis in

Conclusions

The interpretation of studies on vitamin D needs an appreciation of assay variability and the controversies surrounding appropriate serum 25-hydroxyvitamin D reference ranges. Vitamin D has both immunosuppressive and immunostimulatory effects, and ultraviolet radiation, an important confounder, has mainly immunosuppressive effects. Whereas historical literature on phototherapy supports the use of vitamin D in patients with tuberculosis, direct mycobactericidal actions of exposure to ultraviolet

Search strategy and selection criteria

We searched PubMed for articles published in English from 1913 to Nov 2012, using the search terms “tuberculosis”, “vitamin D”, and “ultraviolet radiation”. We sourced further articles from our personal databases, and from references cited in papers identified through the process above.

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      Interestingly, a recent study showed that vitamin D deficiency was strongly associated with extrapulmonary TB (Pareek et al., 2015). On the basis of these findings, vitamin D supplementation could be kept under consideration for specific population groups, such as MDR/XDR-TB or extrapulmonary TB patients; these groups are expected to increase in Europe (Ralph et al., 2013; Sotgiu et al., 2017a, b; Mondoni et al., 2018a, b; Brighenti et al., 2018). Remarkably, individuals with extrapulmonary disease were those for whom heliotherapy and phototherapy were effective (Scolari, 1936; Palmieri, 1936; Vacchelli, 1936; Jarrett, 2017; McCullough and Lehrer, 2018).

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      Vit D appears to be crucial for macrophage activation and early Mtb clearance [14–16]. Vit D enhances innate immunity through TLR and IFN-γ, reversal of phagosome maturation arrest, increased expression of various antimicrobial peptides, and induction of autophagy in infected cells, thus restricting Mtb intracellular growth in macrophages [17]. We herein show that Mtb nucleic acid of different lineages elicit differential inflammatory responses in human macrophages.

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