n a double-blind manner (p<0.001). Candida skin-test results were considered positive if the average diameter of induration was >5 mm (1), and 78% of Candida skin-test results associated with zinc application were positive, compared with 64% with placebo cream (p = 0.01). Zinc-mediated TB and Candida skin-test augmentation were associated (R = 0.3, p = 0.05), but zinc-mediated Candida skin-test augmentation was not significantly associated with any of the variables in the Table.
The control skin tests with placebo cream yielded larger reactions (p = 0.005) and were more likely to be positive (p = 0.005) than concurrent skin tests on 97 other randomly selected healthy volunteers in the same community (data not shown). These 97 skin tests were each performed on 1 arm only, and no creams were applied; the mean diameter of induration was 16.4 mm (SEM 1.9 mm), and 52% were TB skin-test positive (>10 mm). Although the design of this part of the study prevented blinded assessment, this comparison implies that in the 50 persons with simultaneous bilateral skin tests, zinc absorption through the skin may have partially augmented the contralateral control skin-test reactions to which placebo cream was applied. Although the local direct effect at the site of zinc cream application was significantly greater, systemic zinc absorption may have caused the effect of zinc cream to be underestimated; this hypothesis is being further investigated.
Zinc status is difficult to reliably assess (2–4). However, low plasma zinc significantly predicted small skin-test reactions and the magnitude of the immunologic response to topical supplementation. Thus, zinc cream had a specific effect, namely, reversing the skin-test suppression of zinc deficiency. Topical zinc supplementation applied to the arms of persons who received TB skin tests therefore identified persons in whom zinc deficiency was sufficient to suppress antimycobacterial immune responses and quantified the immune-potentiating effect of supplementation. This approach may similarly facilitate the therapeutic evaluation of other micronutrients and immunomodulatory compounds.
Zinc cream had no effect in persons with adequate concentrations of zinc; however, persons who were deficient in zinc but otherwise apparently healthy had suppressed skin-test reactions, despite the absence of frank malnutrition; this suppression was reversed by the application of zinc cream. Thus, zinc cream application corrected false-negative TB skin-test reactions caused by zinc deficiency, allowed more sensitive diagnosis, and hence facilitated appropriate treatment of latent TB infection. Topical zinc is a simple and relatively inexpensive method of enhancing reliability of the established TB skin test for diagnosing this neglected disease. This has public health implications because the TB skin test is central to the problematic area of diagnosing TB infection and disease, especially in children who are prone to both zinc deficiency (2,4) and false-negative skin-test results (1). Therefore, the zinc-mediated augmentation of TB skin testing that we have demonstrated may facilitate the diagnosis of adult and pediatric cases of TB in regions where micronutrient deficiency is prevalent.
In conclusion, this study demonstrated that physiologically significant subclinical zinc deficiency was common in this population, that low plasma zinc predicted negative TB skin-test results, and that topical zinc supplementation augmented local antimycobacterial immune responses sufficiently to reverse this anergy of micronutrient deficiency.
Dr Rao is a physician specializing in international public health practice and research.
We thank the volunteers of Susana Higushi community, who generously gave written informed consent to have paired skin tests for medical research; Tom Doherty, Barbara Golden, and Mayuko Saito for helpful discussions; and Katherine Sacksteder for editorial assistance.
C.A.E. and A.R.E. are funded by the Wellcome Trust. C.A.E. and this research were funded in part by the charity Innovation for Health and 