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Tuberculin and Anergy Testing in HIV-Seropositive and HIV-Seronegative Persons

Norman Markowitz, MD; Nellie I. Hansen, MPH; Timothy C. Wilcosky, PhD; Philip C. Hopewell, MD; Jeffrey Glassroth, MD; Paul A. Kvale, MD; Bonita T. Mangura, MD; Dennis Osmond, PhD; Jeanne M. Wallace, MD; Mark J. Rosen, MD; and Lee B. Reichman, MD, MPH
[+] Article, Author, and Disclosure Information

Pulmonary Complications of HIV Infection Study Group* Requests for Reprints: Norman Markowitz, MD, Henry Ford Hospital, Division of Infectious Diseases, 2799 West Grand Boulevard, Detroit, MI 48202. Grant Support: In part by contracts N01-HR7-6029, 6030,-6031, 6032,-6033, 6034,and 6035 with the National Heart, Lung, and Blood Institute. Co-sponsored by the National Institute of Allergy and Infectious Diseases, National Institutes of Health.

Copyright 2004 by the American College of Physicians

Ann Intern Med. 1993;119(3):185-193. doi:10.7326/0003-4819-119-3-199308010-00002
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Objective: To determine the prevalence and predictors of reactivity to tuberculin purified protein derivative (PPD) and skin test anergy in patients with human immunodeficiency virus (HIV) infection and in HIV-seronegative controls.

Design: Cross-sectional analysis of baseline data from a prospective, multicenter study of pulmonary complications of HIV infection.

Setting: Community-based cohort of persons with and without HIV infection.

Patients: A total of 1171 HIV-seropositive patients without AIDS (841 homosexual men, 274 intravenous drug users, and 56 women with heterosexually acquired infection); 182 HIV-seronegative persons (125 homosexual men and 57 intravenous drug users).

Measurements: Delayed-type hypersensitivity response to tuberculin PPD, trichophytin, mumps, and Candida antigens; T-lymphocyte subsets.

Results: The prevalence of tuberculin PPD reactivity was higher among intravenous drug users than among homosexual men, in both HIV-seronegative (19.1% compared with 6.8%, P = 0.03) and HIV-seropositive persons (15.1% compared with 2.5%, P < 0.001). Among HIV-infected patients, the prevalence of tuberculin reactivity varied directly and that of anergy inversely with the absolute CD4 lymphocyte count. Prevalences were 1% and 72%, respectively, in patients with fewer than 200 CD4 cells/mm3, and 8.4% and 25.5%, respectively, in those with 600 CD4 cells/mm3 (P < 0.001 for both comparisons). Patients with HIV infection and fewer than 400 CD4 lymphocytes/mm3 had a lower prevalence of PPD reactivity than HIV-seronegative controls (2.7% compared with 10.0%, P < 0.001). The strongest predictors of tuberculin reactivity were intravenous drug use, black race, a previous positive PPD test result, and a history of CalmetteGurin bacillus vaccination. The strongest predictor of anergy was HIV seropositivity.

Conclusions: The response to delayed-type hypersensitivity antigens depends on immune status. The value of PPD and anergy testing in HIV-seropositive patients depends on the ability of such testing to predict subsequent tuberculosis, which is imprecisely known. Until more data or better methods are available, these tests should be done as early as possible in the course of HIV infection.

*For participating institutions and investigators, see the Appendix.


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Figure 1.
Effect of varying the induration cutoff for test positivity on delayed-type hypersensitivity response rates.3333

The top panel shows the prevalence of a positive tuberculin purified protein derivative test result based on an induration diameter of 0, 5, or 10 mm. The bottom panel shows the prevalence of a positive mumps antigen reaction based on an induration diameter of 0, 5, or 10 mm. Women with heterosexually acquired human immunodeficiency virus (HIV) were excluded from the analysis. Participants were stratified by CD4 cell count as follows: 0 to 199 cells/mm (200 participants); 200 to 399 cells/mm (298 participants); 400 to 599 cells/mm (282 participants); and 600 cells/mm or more (232 participants). The study included 1012 HIV-positive patients and 160 HIV-negative participants. Prevalences were directly adjusted for differences in the distribution of homosexual men and intravenous drug users within each group. PPD = purified protein derivative.

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Figure 2.
Relation between delayed-type hypersensitivity response rates and immune function in homosexual men, intravenous drug users, and the total cohort.Candida

The top panel shows the prevalence of a positive tuberculin PPD test result ( 10 mm of induration for HIV-negative controls and 5 mm of induration for HIV-positive patients). The bottom panel shows the prevalence of anergy (0 mm of induration for PPD, mumps antigen, and antigen tests). Sample size is indicated above each bar. HIV = human immunodeficiency virus; HIV = homosexual men; IDU = intravenous drug users.

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Figure 3.
Multiple antigens and the prevalence of reactivity.nnCandidaCandida

A subset of 716 participants had all four skin tests. Each set of three bars shows the distribution of tuberculin purified protein derivative (PPD) responses in relation to those for successive batteries of delayed-type hypersensitivity control antigens in human immunodeficiency virus (HIV)-seropositive patients ( = 623) and HIV-seronegative controls ( = 93). The height of each defined segment within a bar indicates the prevalence of each response (expressed as a cumulative percentage). The number associated with each segment indicates the number of persons who had that response. A PPd-positive response and a PPd-negative response were defined as induration 5 mm and <5 mm, respectively, for HIV-seropositive patients and induration 10 mm and <10 mm for HIV-seronegative controls. Induration greater than 0 mm defined a positive reaction to a control antigen. In the battery including all four antigens, PPD positivity was the only response in 21 participants (2.9%); mumps antigen positivity was the only response in 115 (16.1%); antigen positivity was the only response in 78 (10.9%); and trichophytin positivity was the only response in 25 (3.5%). MP = mumps; Cd = ; and Tr = trichophytin.

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