Volume 13, Number 7—July 2007
Zinc Cream and Reliability of Tuberculosis Skin Testing
In 50 healthy Peruvian shantytown residents, zinc cream applied to tuberculosis skin-test sitescaused a 32% increase in induration compared with placebo cream. Persons with lower plasma zinc had smaller skin-test reactions and greater augmentation with zinc cream. Zinc deficiency caused false-negative skin-test results, and topical zinc supplementation augmented antimycobacterial immune responses enough to improve diagnosis.
Tuberculosis (TB) kills >1.7 million people each year, and control is hampered by diagnostic difficulties. The TB (Mantoux) skin test measures the immune response to an intradermal injection of tuberculin (purified protein derivative [PPD]) and is important for diagnosing adult and particularly pediatric TB (1). However, reliability of this skin test is limited by false-negative results (2–4), especially in poorly nourished people in the resource-limited settings where most cases of TB occur (2). Zinc is implicated in false-negative skin tests because it modulates cutaneous reactions (2,3), because zinc deficiency is common in people with TB (5), and because this deficiency also suppresses antimycobacterial immunity (4,5). We therefore studied whether topical application of zinc to TB skin test sites would augment test results in Lima, Peru, a TB-endemic area in which false-negative skin-test results are frequent (1).
After ethical approval and informed written consent were obtained, venous blood was collected from 50 healthy, randomly selected, adult shantytown resident volunteers. Plasma zinc concentrations were analyzed blindly by atomic absorption spectroscopy; precautions were taken against trace-metal contamination. In each study participant, the volar surface of both forearms was injected proximally with tuberculin (5 U in 0.1 mL; Aventis-Pasteur, Toronto, Canada) and distally with Candida albicans antigen (5 U; Hollister Stier Laboratories, Spokane, WA, USA) (1), totaling 4 simultaneous skin tests per person. Candida skin tests were conducted because, when positive, they confirm that the person can mount a cutaneous hypersensitivity reaction, which clarifies that a simultaneous negative TB skin-test result is likely to be a true negative.
In a randomized double-blind manner, skin-test sites on 1 arm were covered with 1 mL of placebo cream (Aqueous cream BP, Sandoz, Bordon, Hants, UK) and the skin-test sites on the contralateral arm were covered with zinc sulfate (2) dissolved in aqueous cream to a concentration of 1% elemental zinc. Each skin test site was immediately covered with an occlusive dressing (Tegaderm, 3M, London, UK). After 24, 48, and 72 h, the dressing and cream were removed, and the “ball-point-pen” test was used to measure induration. The appropriate cream was reapplied and covered after each measurement.
SPSS version 11.5 (SPSS Inc., Chicago, IL, USA) was used for statistical analysis. Except where otherwise stated, the results of skin tests are those read after 48 h. Continuous data were all normally distributed (except for food frequencies) and were therefore summarized as means (and standard errors of the mean [SEM]). Groups were compared by using t tests, and associations were tested by using univariate linear regression (p value and standardized coefficient shown) and in a backward multiple linear regression model with the least significant variables sequentially removed, according to the log-likelihood test.
Control TB skin-test areas to which placebo cream had been applied yielded significantly smaller reactions in persons with lower concentrations of plasma zinc (p = 0.03, Table). For example, the quarter of the population with the lowest concentrations had, on average, control TB skin-test reactions that were 14 mm in diameter compared with 27 mm for the quarter of the population with the highest plasma zinc concentrations (p = 0.03). This immunologically significant zinc deficiency was frequent even though only 10% of the study population was underweight (body mass index <20 m2/kg)