TB, BCG, PPD, and Travelers

Abstract & Commentary

Synopsis: In low-risk populations, positive tuberculin skin tests (TST, purified protein derivative, PPD) might be due to previously received tuberculosis (TB) vaccine (Bacille Calmette-Guerin, BCG), rather than to latent tuberculosis infection. In travelers and other higher risk groups, however, positive tests should suggest infection.

Source: Tissot F, et al. Influence of Bacille Calmette-Guerin Vaccination on Size of Tuberculin Skin Test Reaction: To What Size? Clin Infect Dis. 2005;40:211-217.

The interpretation of tuberculin skin tests is challenging and controversial, especially in the face of previously administered BCG vaccine. In Switzerland, a country where TB infection is not common but where BCG had previously been routinely given, Zysset and colleagues prospectively evaluated 2-step (second test done 8-15 days after the first for possible booster effect) TST results in 5117 hospital employees, in view of potential risk factors for TB infection.

On initial testing, 40% had TST results greater than or equal to 10 mm, and an additional 400 of the 2764, who initially had negative results, were positive on the second-step testing. Thus, a total of 48% had positive results. On multivariate analysis, the influence of BCG vaccination on TST results varied across age categories. Vaccination was the strongest predictor of a positive result up to age 40 years. The influence of BCG vaccination on TST results was less significant when only results of 18 mm or greater were considered. Having been subjected to 5 or more previous TSTs was also an independent risk factor for having a positive result. After careful, statistical analysis, Zysset et al conclude that "except for persons who have never been vaccinated, TST reactions of up to 18 mm in diameter in persons less than 40 years old are more likely to be the result of prior vaccination than of infection, and should not systematically lead to preventive chemotherapy." How do we view such a statement?

Comment by Phillip R Fischer, MD, DTM&H

BCG vaccine is effective in decreasing the risk of extra-pulmonary TB, but seems less effective in altering the risk of pulmonary disease.1 The vaccine is nearly impossible to find in the United States, but immigrants from other countries have often been vaccinated. In fact, BCG vaccination is still routinely used in 161 countries.2

The interpretation of TST results is fraught with controversy. Several studies, particularly those done in children in areas of high TB prevalence, suggest that the influence of BCG on TST results is significant, but that it wanes over time.3,4,5 In the United States, the Centers for Disease Control and Prevention advise that previous BCG vaccination history should not affect the interpretation of a TST result in someone who is at risk of recent infection.6

With this in mind, the Swiss data summarized above provide fuel for ongoing discussions. Positive reactions measuring between 10 and 18 mm in young adults seemed to be more likely due to BCG vaccination than to latent infection. Zysset et al’s recommendation to limit treatment for latent tuberculosis among these positive individuals seems appropriately data-driven.

Nonetheless, American practitioners of travel medicine are seeing a patient population that is vastly different from the group studied in Switzerland. Many of the Swiss subjects in the study had no history of travel to or from an area endemic for tuberculosis, or of exposure to a patient with TB; their only risk factors for positive TST were the BCG vaccination and previous TST.

Travel medicine providers typically see patients who have emigrated from TB-endemic areas or who are traveling to and from areas wherein there is significant risk for tuberculosis exposure. Thus, travel medicine providers see individuals with clear-cut risk factors for TB, and attribution of a positive result to a past BCG vaccine would involve discounting the very real possibility of actual TB exposure and infection.

In the same issue of Clinical Infectious Diseases, in which the Swiss study appears, Dr. Laurie Miller reviews infectious disease issues relevant to international adoption.7 She points out that there is no reliable method to distinguish positive TST reactions caused by BCG vaccination from those caused by infection, and reminds readers that experts agree prior vaccination should influence neither the interpretation of these reactions nor the decision of whether to treat the subject.

The Swiss might reasonably discuss whether this is true for healthy young adults with no other risk factors, but their data should not change the application of current expert opinion and practice for immigrant children and adults, for international travelers, and for people potentially exposed to someone with active TB. At least in these populations, positive TST results should still prompt further evaluation for active TB and, if no active disease is found, consideration of therapy for latent TB infection, regardless of whether or not the individual received BCG vaccination.

References

1. Colditz GA, et al. Efficacy of BCG Vaccine in the Prevention of Tuberculosis: Meta-Analysis of the Published Literature. JAMA. 1994;271:698-702.

2. World Health Organization. Vaccines, Immunization, and Biologicals. www.who.int/vaccines/globalsummary/immunization/ScheduleResult.cfm, accessed 3-4-05.

3. Chee CBE, et al. Interpretation of the Tuberculin Skin Test in Mycobacterium bovis BCG-Vaccinated Singaporean Schoolchildren. Am J Respir Crit Care Med. 2001;164:958-961.

4. Lienhardt C, et al. Risk Factors for Tuberculosis Infection in Sub-Saharan Africa. Am J Respir Crit Care Med. 2003;168:448-455.

5. Wang L, et al. A Meta-Analysis of the Effect of Bacille Calmette Guerin Vaccination on Tuberculin Skin Test Measurements. Thorax. 2002;57:804-809.

6. American Thoracic Society, Centers for Disease Control and Prevention. Targeted Tuberculin Testing and Treatment of Latent Tuberculosis Infection. Am J Respir Crit Care Med. 2000;161:S221-247.

7. Miller LC. International Adoption: Infectious Disease Issues. Clin Infect Dis. 2005;40:286-293.