ESAT-6/CFP10 Skin Test Predicts Disease in M-tuberculosis-Infected Guinea Pigs

Background: Targeted preventive chemotherapy of individuals with progressive subclinical (incipient) disease before it becomes contagious would break the chain of tuberculosis transmission in high endemic regions. We have studied the ability of a skin test response to ESAT-6 and CFP10 (E6/C10) to predict later development of tuberculosis disease in the guinea pig model. Methods and Findings: Guinea pigs, either vaccinated with BCG or unvaccinated, were infected with a low dose of Mycobacterium tuberculosis by the aerosol route and the development of delayed type hypersensitivity responses to E6/C10 and to purified protein derivative (PPD) were followed until the onset of clinical disease. We demonstrated a negative correlation between the size of the skin test response and the time to the onset of clinical disease; a large E6/C10 skin test response correlated to a shorter survival time post skin testing, while a small E6/C10 skin test reaction correlated with a longer survival time (r = 20.6 and P < 0.0001). No correlation was found using PPD. Conclusions: Our data suggest that it may be possible to develop a prognostic skin test based on E6/C10 that will allow the identification of individuals with incipient disease, who have the highest risk of developing active tuberculosis in the near future.