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No. 2, 2014

The Tuberculin Skin Test and the Risk of Death Among Patients With Active TB

In 1890, Dr. Robert Koch announced he had found a cure for TB: the tuberculin protein. Despite falling short of that initial claim, over the last 120 years, the tuberculin skin test (TST) has been widely adopted to screen for infection with TB and to identify latently infected individuals who may benefit from TB preventive therapy.1 However, it is important to remember that the TST is not a perfect test. The induration that is measured as the “readout” of a TST is dependent upon not only the presence of the tuberculin protein, but also the host immune response to the tuberculin.

Approximately 10%–25% of patients with TB disease have a negative TST result.2,3 Patients with TB disease who have a negative TST result are unable to mount the host immune response necessary to generate induration. Young children and people with HIV infection who develop TB disease are more likely to have a negative TST and more likely to present with severe disease.1 Studies have also found that young children and people with HIV infection who have TB disease and a negative TST result have an increased risk of death.4,5 The association between a negative TST result and death has also been reported in smaller studies of immunocompetent adults, but the nature of this relationship remains poorly understood.6,7

We conducted a study to determine the association between TST result and the risk of death among persons with TB disease in the United States. For the period January 1, 1993, through December 31, 2008, we looked at all cases of TB reported through the National Tuberculosis Surveillance System with a positive TB culture result at baseline and a documented TST result who had either completed TB therapy or died of any cause after initiating therapy. In order to account for many of the factors that are known to influence the host immune system or the TST result, we adjusted our analysis for HIV status, origin of birth (i.e., U.S. born or foreign born), age, sex, location of TB disease (e.g., pulmonary, extrapulmonary), and presence of cavities on chest x-ray. We also examined cases based on their baseline drug-susceptibility test results, using three categories: 1) susceptibility to all four first-line TB drugs (isoniazid, rifampin, pyrazinamide, and ethambutol), 2) resistance only to isoniazid, or 3) multidrug-resistant (MDR) TB with resistance to at least rifampin and isoniazid. We found that patients with TB disease and a negative TST result are two to three times more likely to die than patients with a positive TST result, despite adjusting for important covariates. These findings were consistent across the three drug-susceptibility categories.

Our results are consistent with prior studies suggesting that patients with a negative TST are at greater risk of death; based on this analysis, we recommend using the TST for both routine clinical practice and as a part of TB research activities. In addition to serving as an indicator of latent TB infection, a negative TST result appears to be a marker for risk of death among patients with active TB disease.

Reported by Sara Auld, MD
Div of TB Elimination


  1. Huebner RE, Schein MF, Bass JB. The tuberculin skin test. Clin Infect Dis 1993 Dec;17(6):968-75.
  2. Holden M, Dubin MR, Diamond PH. Frequency of negative intermediate-strength tuberculin sensitivity in patients with active tuberculosis. The New England Journal of Medicine 1971 Dec-30;285(27):1506-9.
  3. Nash D, Douglass J. Anergy in active pulmonary tuberculosis. A comparison between positive and negative reactors and an evaluation of 5 TU and 250 TU skin test doses. Chest 1980;77(1):32-7.
  4. Whalen CC, Nsubuga P, Okwera A, Johnson JL, Hom DL, Michael NL, et al. Impact of pulmonary tuberculosis on survival of HIV-infected adults: a prospective epidemiologic study in Uganda. AIDS 2000 Jun 16;14(9):1219-28.
  5. Drobac PC, Shin SS, Huamani P, Atwood S, Furin J, Franke MF, et al. Risk factors for in-hospital mortality among children with tuberculosis: the 25-year experience in Peru. Pediatrics 2012 Aug;130(2):E373-E9.
  6. Delgado JC, Tsai EY, Thim S, Baena A, Boussiotis VA, Reynes JM, et al. Antigen-specific and persistent tuberculin anergy in a cohort of pulmonary tuberculosis patients from rural Cambodia. Proceedings of the National Academy of Sciences of the United States of America 2002 May 28;99(11):7576-81.
  7. Sousa AO, Salem JI, Lee FK, Vercosa MC, Cruaud P, Bloom BR, et al. An epidemic of tuberculosis with a high rate of tuberculin anergy among a population previously unexposed to tuberculosis, the Yanomami Indians of the Brazilian Amazon. Proceedings of the National Academy of Sciences of the United States of America 1997 Nov 25;94(24):13227-32.

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