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Persistence and Boosting of Bacille Calmette-Guérin–Induced Delayed-Type Hypersensitivity

Daniel F. Hoft, MD, PhD; and Jan M. Tennant, RN
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From Saint Louis University Health Sciences Center, St. Louis, Missouri.

Acknowledgments: The authors thank the volunteers who participated in the BCG trials and the nursing staff involved in recruitment and assessment of volunteers; Edwin Anderson, MD, William Banton III, MD, MPH, Robert Belshe, MD, Donald Kennedy, MD, Raymond Slavin, MD, and Vic Tomlinson, MPA, for critical review of this manuscript and helpful discussions; and Sharon Homan, PhD, and Mark VanRaden, MA, for biostatistical support.

Grant Support: By Vaccine Treatment & Evaluation Unit contract NO1-AI-45250 from the National Institutes of Health. Connaught Laboratories, Ltd. (North York, Ontario, Canada), and Perimmune, Inc. (Rockville, Maryland), supported the original vaccine trials, and Connaught Labs provided purified protein derivative for the two-step follow-up protocol.

Requests for Reprints: Daniel F. Hoft, MD, PhD, Division of Infectious Diseases and Immunology, Saint Louis University Health Sciences Center, 3635 Vista Avenue, FDT-8N, St. Louis, MO 63110; e-mail, hoftdf@slu.edu.

Current Author Addresses: Dr. Hoft and Ms. Tennant: Division of Infectious Diseases and Immunology, Saint Louis University Health Sciences Center, 3635 Vista Avenue, FDT-8N, St. Louis, MO 63110.

Ann Intern Med. 1999;131(1):32-36. doi:10.7326/0003-4819-131-1-199907060-00007
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Background: Bacille Calmette-Guérin (BCG) vaccination may induce persistent and booster purified protein derivative (PPD) responses that complicate tuberculosis screening efforts.

Objectives: To investigate the effects of BCG vaccination on serial PPD tests and to study correlations between persistent delayed-type hypersensitivity and other potential surrogate markers of protective immunity.

Design: Cohort study.

Setting: Midwestern urban university.

Participants: 69 healthy adults.

Interventions: BCG vaccination, blood samples drawn for immunologic studies, and PPD tests done sequentially over 1 to 3 years.

Measurements: Serial PPD induration, lymphoproliferation, and interferon-γ responses.

Results: 10% of participants (95% CI, 4% to 20%) had persistent PPD responses of 15 mm or greater, and 3% (CI, 0% to 10%) demonstrated PPD boosting of 15 mm or greater 1 to 3 years after BCG vaccination. Intradermal BCG vaccination induced a larger number of persistent responses that were 10 mm or greater than did percutaneous BCG vaccination (12 of 46 participants compared with 1 of 23 participants; P = 0.05). Persistent and boosted delayed-type hypersensitivity correlated with mycobacterial-specific lymphoproliferation and interferon-γ responses.

Conclusions: Previous BCG vaccination reduces the predictive value of serial PPD testing. The lowest PPD predictive values will occur in persons without known tuberculosis exposure who were vaccinated recently or many times with intradermal BCG. In addition, BCG-related persistence and boosting of delayed-type hypersensitivity responses correlate with other potential surrogate markers of protective mycobacterial immunity.


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Correlations between type 1 immunity induced by bacille Calmette-Guérin (BCG) vaccination and delayed-type hypersensitivity responses studied 1 to 3 years after vaccination.PPDnwhite symbolsnblack symbolscirclessquaressolid linedotted linerPrP

Purified protein derivative ( ) responses (in millimeters of induration 48 to 72 hours after administration of 5 tuberculin units) measured during two-step PPD testing done 1 to 3 years after BCG vaccination are plotted against mycobacterial-specific lymphoproliferative ( = 32; ) and interferon-γ (IFN-γ) ( = 15; ) responses measured in peripheral blood mononuclear cells harvested 2 months after vaccination. The PPD2 responses ( ) were measured during the first step of two-step testing and represent persistent PPD responses detectable 1 to 3 years after BCG vaccination. The PPD3 responses ( ) were measured during the second step of two-step testing and represent boosted responses 1 to 3 years after BCG vaccination. The straight lines are the fitted least-squares regression lines for lymphoproliferation ( ) or interferon-γ responses ( ) compared with PPD3 responses. The correlation coefficients were calculated by using the Spearman rank-order statistic to minimize the influence of outlying points ( = 0.4 and = 0.04 for lymphoproliferation compared with PPD3; = 0.6 and = 0.04 for interferon-γ compared with PPD3).

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