The main objective of this large study is to determine whether six months of daily micronutrient supplementation with combined zinc, vitamin A and vitamin D protects household contacts of those with active, infectious TB from themselves contracting TB. Micronutrients or a placebo are consumed for the six months following exposure to the initial case, and surveillance for secondary cases of TB continues for the duration of the study.

Over three years, our team has identified and visited 1,802 households in which a patient with sputum microscopy-positive pulmonary tuberculosis was diagnosed by our collaborators in the Peruvian National TB program. Interim results have already provided important public health discoveries concerning determinants of TB susceptibility and transmission from patients to contacts, demonstrating statistically and biologically significant effects of these micronutrients in the enhancement of antimycobacterial immunity. We outline several groundbreaking findings below, which have the potential for important practical application as we work towards translating them into application in resource-poor communities.

Finding 1: Oral micronutrients augment TB skin tests. The ongoing micronutrient study involves optional tuberculin (PPD) TB skin tests before and during daily micronutrients/placebo. We demonstrated that oral micronutrient supplementation causes a significant increase in TB skin test size after oral zinc, vitamin A and D supplementation. This effect was greatest in those with evidence of poorest nutrition, implying that poor nutrition impairs the reliability of the TB skin test, and that these false-negative TB skin tests may be corrected with micronutrient supplementation. This micronutrient-mediated augmentation of the TB-skin test has clinical as well as epidemiological implications because this test is widely used to facilitate the diagnosis of TB disease, particularly in children.

Finding 2: Malnutrition impairs TB immunity. We found that individuals with correlates of malnutrition had smaller TB skin tests, implying an impaired response to this test. In addition, because the TB skin test is thought to correlate to immunity against TB, malnutrition may suppress TB immunity, suggesting that vitamins may increase protection against TB.

Finding 3: Topical zinc supplementation augments TB immunity. Fifty shantytown residents had simultaneous skin tests on both forearms. Zinc cream applied to one side caused a significant increase in TB skin test positivity; this phenomenon was significantly more pronounced in those with low blood zinc levels.This research demonstrates that zinc deficiency is common in this population and topical zinc supplementation augments the TB skin test response, reversing the suppression resulting from malnutrition.

Finding 4: Transient TB susceptibility. Characterization of the TB strain responsible for disease of index case and contact strains demonstrated that strains are identical in only 64% of cases; this is surprising, because one might expect that household contacts who get TB generally contract it from the index case. However, this is concordant with some other studies that imply that transient factors cause locally increased susceptibility, causing some household contact cases of TB that have been misattributed to household transmission. We are testing the hypothesis that these transient factors are principally caused by inadequate nutrition.

Finding 5: Micronutrient deficiency in TB patients. We investigated malnutrition in newly-diagnosed TB patients and monitored nutritional status during treatment. Body mass index (BMI) in patients was significantly lower in patients than in controls, and increased significantly with therapy. TB patients had lower blood vitamin A concentrations than those without TB, and those deficient in vitamin A had a delayed response to therapy, suggesting that vitamin A deficiency impairs anti-TB immunity. These results suggest that  malnutrition impairs treatment response, and that vitamin supplementation may increase both protection against TB disease and response to TB treatment.

Finding 6: Response to regular therapy of those with drug-resistant TB. The typical chemotherapy designed to treat drug-sensitive TB has been reported to cure up to 60% of patients with drug-resistant TB. However, we demonstrated that these patients are not permanently cured; many relapse to active, infectious TB, and infect significantly more of their household contacts than those with drug-susceptible TB. These results suggest that while many patients with unrecognized drug-resistant TB are apparently cured by normal TB therapy, they have prolonged infectiousness during treatment, encouraging  the spread of drug-resistant TB. This underscores the importance of early diagnosis and proper treatment of drug-resistant TB.

---