Vitamin D in Active Tuberculosis (TB) Study

1.0 Introduction and Background

Tuberculosis remains an enormous public health problem and a major cause of morbidity and mortality throughout the world. The WHO estimates that 8.8 million new cases of tuberculosis occurred worldwide in 2005, along with 1.6 million TB related deaths. New challenges in TB control include the HIV epidemic, as well as the emergence of multidrug resistant (MDR) and extremely drug resistant (XDR) strains of tuberculosis which are associated with high morbidity and mortality. While cure rates for drug susceptible TB can reach the >90% range given the appropriate infrastructure to diagnose and treat patients, cure rates for MDR-TB are much lower and, at best, approach 60% according to the latest estimates by WHO. In many parts of the world, second line drugs to treat MDR-TB are not available. Not only is there an urgent need for novel TB treatment regimens, but adjunctive therapeutic modalities need to be explored with the goal of maximizing clinical response for both patients with drug susceptible and drug resistant disease.

The use of vitamin D as primary or adjunctive TB therapy has a long history. Therapeutic doses of oral vitamin D supplementation for TB treatment were first pioneered in the 1950's by Jacques Charpy, who noted excellent results in cutaneous TB disease. Subsequently, vitamin D has been used as both primary and adjunctive therapy in pulmonary tuberculosis, but this practice fell out of favor as effective antimycobacterial chemotherapy became widely available in the latter half of the twentieth century.

More recently, however, there has been a resurgence of interest in vitamin D as an effective adjunctive therapy in tuberculosis. Recent reports indicate that vitamin D may have a pronounced immunomodulatory role in the pathogenesis of tuberculosis within the human host. It is well known that areas of granulomatous inflammation in TB are sites of increased vitamin D production stemming from activated macrophages and Th1 lymphocytes within the granuloma Recently, the immunomodulatory function of increased vitamin D levels at sites of TB involvement has been demonstrated, in that 1,25(OH)2D, the active metabolite form of vitamin D, has been found to induce antimycobacterial activity in vitro in both monocytes and macrophages.

One proposed pathway for this observed immunomodulatory effect of vitamin D in TB infection involves the toll-like receptor (TLR) signaling pathways of the innate immune system. Liu et al demonstrated that macrophage TLR binding of M. tuberculosis antigen upregulates the expression of cellular 1 hydroxylase, resulting in higher levels of active 1, 25(OH)2D. It was also shown that 1, 25(OH)2D in turn binds the nuclear vitamin D receptor (VDR), which activates a downstream signaling cascade resulting in the upregulation of several aspects of the innate immune response, including the induction of a newly described anti-microbial peptide LL-37, a cathelicidin. Cathelicidins, in addition to their broad spectrum antimicrobial activity, also possess chemotactic properties for neutrophils, monocytes and T cells, among other functions within the immune system.

While this mechanism of action for vitamin D was demonstrated in vitro, little clinical work has been done to validate this piece of knowledge in clinical practice and in the care of TB patients. As proxy for in vivo studies, subsequent experiments by Liu et al evaluated induction of cathelicidin by TLR activation of macrophages in sera from African American and Caucasian subjects. These experiments demonstrated failure to induce detectable levels of cathelicidin mRNA in samples from African American patients, who are known to be significantly more vitamin D deficient than Caucasians due to difference in vitamin D production in the skin. The difference in cathelicidin mRNA levels was corrected upon supplementation of deficient sera to therapeutic levels of 25(OH)D3 prior to TLR stimulation.

Given the preliminary results of these in vitro studies, we propose a clinical pilot investigation of the relationship between vitamin D levels and cathelicidin production in TB patients. It is well known that the majority of TB patients are deficient in vitamin D, but it is unknown whether the deficiency has functional consequences for treatment response and relapse rates. While recent in vitro data suggests that vitamin D supplementation of recent TB contacts does improve their immune response to Mycobacterium tuberculosis as measured in whole blood assays, clinical trials of vitamin D supplementation in latent or active TB disease have not been undertaken. In preparation for larger trials that would be needed to address this clinical question, we propose that the clinical relationship between physiologic levels of vitamin D supplementation and effect on cathelicidin production within the host needs to be studied, given recent suggestions from in vitro studies that ability to generate adequate cathelicidin levels may have an impact on quality and effectiveness of host immune defense against M. tuberculosis.

2.0 Objectives

2.1 Overall Objective

The primary objective of this pilot study is to assess the relationship of 25-hydroxy vitamin D levels in patients with active pulmonary tuberculosis to levels of LL-37/cathelicidin in sputum, saliva, and whole blood.