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International Notes Tuberculin Reactions in Apparently Healthy HIV-Seropositive and HIV-Seronegative Women -- Uganda

Persons latently infected with Mycobacterium tuberculosis are at substantially increased risk for developing clinically apparent tuberculosis (TB) if they become infected with human immunodeficiency virus (HIV) (1,2). Although skin testing with purified protein derivative (PPD) by the Mantoux method is a standard method of screening for tuberculous infection, this method may be hampered by nonreactivity to skin tests of persons who become immunosuppressed because of progressive HIV infection. In Uganda, a continuing study of HIV infection in postpartum women, conducted by the Ministry of Health in collaboration with Case Western Reserve University, provided an opportunity to study the tuberculin reactivity of apparently healthy women of known HIV serologic status. This report presents data from the Uganda study. In 1988-89, approximately 95% of 2000 pregnant women presenting to Mulago Hospital in Kampala for uncomplicated delivery volunteered to participate in a prospective study of HIV infection. Serum specimens obtained from these participants were tested for HIV antibody by enzyme-linked immunosorbent assay (ELISA) using Recombigen-HIV EIA Kits* (Cambridge BioScience, Worcester, Massachusetts). All seropositive women and a random sample of seronegative women were then enrolled in the study. During the postpartum period, women were tuberculin tested by the Mantoux technique using Old Tuberculin (OT) 1:2000 (equivalent to 5 tuberculin units (TU) of PPD) with Tuberculin "GT"* (Behringwerke AG, Marburg, Federal Republic of Germany) (this preparation is used by the Tuberculosis Control Program of Uganda). All tuberculin tests were applied and read by the same trained technician who did not know the HIV status of participants. All reactions were measured at 48 hours with a millimeter rule and recorded as the mean of two perpendicularly intersecting diameters of induration. Results were available for analysis for 94 women (33 HIV-seronegative and 61 HIV-seropositive), all of whom appeared healthy and had no signs or symptoms attributable to HIV infection or opportunistic infection. Of the 33 HIV-seronegative women, 27 (82%) had tuberculin skin test reaction sizes greater than or equal to 3 mm (the diameter the Ministry of Health selected as a cutpoint), and the median reaction size for this group was 10.6 mm (Figure 1). Of the 61 HIV-seropositive women, 29 (48%) had reactions greater than or equal to 3 mm, and the median reaction size was 7.5 mm (p less than 0.05 for frequency of reactions greater than or equal to 3 mm, chi-square test; p less than 0.01 for difference in medians, Mann-Whitney U test) (Figure 1). All but one patient were examined for a BCG (Bacillus of Calmette and Guerin) vaccination scar. Of 32 HIV-seronegative women, 18 (56%) had a BCG scar; of the 61 HIV-seropositive women, 28 (46%) had a BCG scar. For both HIV-seronegative and HIV-seropositive women, tuberculin nonreactivity was more likely among those without a BCG scar. Among the HIV-seronegative women, two (11%) of 18 with a BCG scar had no detectable tuberculin reaction, compared with four (29%) of 14 without a BCG scar (p=0.17, Fisher's exact test). Among the HIV-seropositive women, seven (25%) of 28 with a BCG scar had no reaction to tuberculin, compared with 25 (76%) of 33 without a BCG scar (p=0.05, Fisher's exact test). However, for HIV-seropositive women with and without BCG scars, the relative risk for tuberculin nonreactivity was similar (2.3 and 2.6, respectively). Reported by: A Okwera, MD, PP Eriki, MD, Ministry of Health, Kampala, Uganda. LA Guay, MD, P Ball, TM Daniel, MD, Case Western Reserve Univ, Cleveland, Ohio. Div of Tuberculosis Control, Center for Prevention Svcs; Div of HIV/AIDS, Center for Infectious Diseases, CDC.

Editorial Note

Editorial Note: The interaction between HIV and the tubercle bacillus has dramatically affected the incidence of TB throughout the world. The recent interruption in the decline of TB cases in the United States is attributed in large part to the occurrence of TB among persons also infected with HIV (3). In some countries in central Africa, where more than half the adult population is infected with the tubercle bacillus, the HIV epidemic has been associated with sharp increases in TB morbidity (4). Based on the frequency of HIV and tuberculous coinfection in Uganda, an estimated excess of 250,000 TB cases could occur in that country during the next 5 years (5). An important intervention to control HIV-associated TB is the administration of isoniazid preventive therapy to coinfected persons. However, the occurrence of HIV-induced anergy to tuberculin hampers both the diagnosis of tuberculous infection and the identification of coinfected persons. The number of women tested in the Uganda study was relatively small, and data to evaluate comparability between HIV-seropositive and HIV-seronegative women regarding other characteristics (e.g., age) were not available. However, the findings suggest that HIV infection can depress tuberculin reactions before signs and symptoms develop. Because additional diagnostic studies (e.g., CD4 cell counts, anergy test panels, beta-2-microglobulin, p-24 antigen levels, or other measures of the stage of HIV disease) were not done in these women, the investigators could not determine whether nonreactivity to tuberculin was associated with more advanced HIV disease. However, a recent study in Florida of patients who were reported as having both TB and acquired immunodeficiency syndrome (AIDS) indicated that the probability of tuberculin anergy was inversely related to the interval between diagnosis of TB and diagnosis of AIDS (6). Tuberculin skin testing in asymptomatic HIV-seropositive and HIV-seronegative intravenous-drug users in Switzerland and in prisoners in Italy also detected lower rates of PPD reactivity among those with HIV infection (7,8). In Italy, the mean CD4 count for those with HIV infection was 569/mm3, and the CD4:CD8 ratio was 0.6:1.0; both of these values were lower than normal. Thus, the reliability of tuberculin skin tests in screening for TB and tuberculous infection may be lower in HIV-infected persons, especially those with low CD4 counts. An important finding in Uganda is that the prior administration of BCG appears to maintain tuberculin reactivity at higher levels than in persons with "natural" mycobacterial infection. Therefore, prior BCG vaccination complicates the interpretation of skin test results and decisions about preventive therapy (9). The Adivsory Committee for Elimination of Tuberculosis and the American Thoracic Society recommend that tuberculin reactions greater than or equal to 5 mm be considered positive in HIV-seropositive persons (regardless of BCG vaccination status) and that such persons be considered for isoniazid prophylaxis (2). Based on the data from Uganda and the other sources cited above, persons with HIV infection and tuberculin skin test reaction sizes less than 5 mm who have evidence of immunosuppression (e.g., CD4 count less than 400/mm3 and/or anergy to other delayed-type hypersensitivity skin test antigens) may also need to be considered for isoniazid preventive therapy; such consideration should also be based on individual clinical and epidemiologic assessments of the likelihood of M. tuberculosis infection. The problem of HIV-related tuberculin anergy among persons in the United States requires further evaluation, and a more sensitive and specific method for diagnosing tuberculous infection among immunosuppressed persons is needed. Studies of the usefulness of CD4 counts or other laboratory parameters in predicting anergy and of the optimal method of determining anergy (e.g., single antigen or anergy panel) are particularly important. CDC will be developing more specific recommendations on anergy testing and the administration of preventive therapy for immunosuppressed persons.

References

  1. Selwyn PA, Hartel D, Lewis VA, et al. A prospective study of the risk of tuberculosis among intravenous drug users with human immunodeficiency virus infection. N Engl J Med 1989; 320:545-50.

  2. CDC. Tuberculosis and human immunodeficiency virus infection: recommendations of the Advisory Committee for the Elimination of Tuberculosis (ACET). MMWR 1989;38:236-8, 243-50.

  3. Rieder HL, Cauthen GM, Kelly GD, Bloch AB, Snider DE. Tuberculosis in the United States. JAMA 1989;262:385-9.

  4. Styblo K. The global aspects of tuberculosis and HIV infection. Bull Int Union Tuberc Lung Dis 1990;65:28-32.

  5. Goodgame RW. AIDS in Uganda--clinical and social features. N Engl J Med 1990;323:383-9.

  6. Rieder HL, Cauthen GM, Bloch AB, et al. Tuberculosis and acquired immunodeficiency syndrome--Florida. Arch Intern Med 1989;149:1268-73.

  7. Robert CF, Hirschel B, Rochat T, Deglon JJ. Tuberculin skin reactivity in HIV-seropositive intravenous drug addicts (Letter). N Engl J Med 1989;321:1268.

  8. Canessa PA, Fasano L, Lavecchia MA, Torraca A, Schiattone ML. Tuberculin skin test in asymptomatic HIV seropositive carriers (Letter). Chest 1989;96:1215-6.

  9. Snider DE. Bacille Calmette-Guerin vaccinations and tuberculin skin tests. JAMA 1985;253: 3438-9. *Use of trade names is for identification only and does not imply endorsement by the Public Health Service or the U.S. Department of Health and Human Services.



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