BCG Vaccination and Pediatric HIV Infection -- Rwanda, 1988-1990

In Africa, tuberculosis (TB) is one of the most common severe diseases associated with human immunodeficiency virus (HIV) infection. For infants in Rwanda and other countries where the risk for TB infection is high, the World Health Organization (WHO) recommends vaccination against TB at birth with bacille Calmette-Guerin (BCG) vaccine (1). This report summarizes a study of the occurrence of immune responses and adverse reactions following BCG vaccination among a cohort of infants born to HIV-seropositive and HIV-seronegative mothers in Kigali, Rwanda, where the prevalence of HIV infection among women of childbearing age is approximately 30% (2).

In November 1988, an ongoing prospective study of the mother-to-infant transmission of HIV type 1 (HIV-1) was initiated in Kigali. Through June 1989, the study enrolled a cohort of 422 newborns who had been vaccinated during the first week of life with a freeze-dried BCG vaccine (Evans Medical Ltd TM *, intradermal injection of 0.05 mL); of these, 209 were born to HIV-1-seropositive mothers, and 213, to HIV-1-seronegative mothers.

During the first 15 months of follow-up, infants were examined every 2 weeks for regional adenitis (BCG-itis) and major side effects (e.g., generalized BCG-itis, meningitis, osteomyelitis, and sepsis). At 6 months of age, the infants were examined for the presence of a BCG scar and were administered a tuberculin skin test (intradermal injection of 0.1 mL of tuberculin, 10 International Units, Institut Pasteur du Brabant TM). The skin test was considered negative if the diameter of the induration was less than 6 mm after 48 hours. Nonreactivity to tuberculin was defined as the total absence of induration to the tuberculin skin test. In addition, at 6 months of age, mononuclear peripheral blood cell subpopulations were quantified by using an indirect immunofluorescence technique and monoclonal antibodies (P. Van de Perre, Reference Laboratory, National AIDS Control Program, Kigali, Rwanda, personal communication, 1991). A T4/T8 ratio of less than 1:1 was considered the criterion for impaired cellular immunity.

Of the 422 children, 18 were either lost to follow-up before the age of 6 months (10 children) or died (eight) before the age of 6 months of causes unrelated to BCG vaccination. The remaining 404 children were classified into four groups based on their probable HIV-infection status and the known HIV serostatus of their mothers (Table 1): group 1 (n=37), infant infected, mother HIV-antibody-positive; group 2 (n=140), infant not infected, mother HIV-antibody-positive; group 3 (n=200), infant not infected, mother HIV-antibody-negative; and group 4 (n=27), infant status undetermined, mother HIV-antibody-positive or infant seroconversion during first 6 months, mother HIV-antibody-negative. Infants in group 4 were excluded from this analysis.

No major side effects occurred during follow-up among the 377 children in groups 1-3. BCG-itis was diagnosed 54 days after vaccination in a child from group 1. Suppuration at the location of injection was reported in one infant from group 1, one from group 2, and four from group 3 (not significant, Fisher's exact test). No other clinical manifestations were reported.

Of the 377 children, 361 (96%) were alive at 6 months of age and were skin tested and examined for the presence of BCG scars. Of the 361, seven did not have scars (three (9%) of 33 in group 1, one (1%) of 136 in group 2, and three (2%) of 192 in group 3) (two-tailed Fisher's exact test of group 1 versus group 3; p=0.04). Tuberculin skin test reactions were measured according to the protocol in 341 (94%) of the 361 children. The proportion of negative skin tests was statistically higher in groups 1 (73%) and 2 (43%) than in group 3 (30%) (Table 2). The mean reaction diameter was substantially smaller in group 1 than in groups 2 and 3 (Table 2). The proportion of children with nonreactivity to tuberculin was significantly higher in group 1 (48%) than in the other groups (Table 2).

A T4/T8 lymphocyte count was performed for 291 (85%) of the 341 children. The proportion with a T4/T8 ratio less than 1:1 at 6 months of age was 61% in group 1 (17/28), 17% in group 2 (19/111), and 9% in group 3 (14/152). Among the children with a T4/T8 ratio less than 1:1, the proportion with nonreactivity to tuberculin was 65% in group 1 (11/17), 16% in group 2 (3/19), and 14% in group 3 (2/14). Among the children with a T4/T8 ratio greater than or equal to 1:1, the proportion with nonreactivity to tuberculin was 45% in group 1 (5/11), 18% in group 2 (17/92), and 9% in group 3 (13/138). Reported by: P Msellati, MD, F Dabis, MD, National Institute of Health and Medical Research, University of Bordeaux II, Bordeaux, France. P Lepage, MD, DG Hitimana, MD, C Van Goethem, MD, Dept of Pediatrics, Hospital Center of Kigali; P Van de Perre, MD, Reference Laboratory, National AIDS Control Program, Kigali, Rwanda.

Editorial Note

Editorial Note: In this study, no cases of disseminated BCG disease were identified following BCG vaccination of newborns -- a finding consistent with other studies in Africa (3,4). In addition, only one case of BCG-itis was observed, which did not appear to be directly associated with HIV infection. Although absence of scarring after vaccination was infrequent, this problem was noted more commonly among HIV-infected children than among the other groups. The proportion of infants with a negative skin test reaction to tuberculin was substantially higher among HIV-infected infants than among the other groups; this finding is similar to results of a study of HIV-infected adults in Uganda (5). These data suggest that tuberculin skin test responses following BCG vaccination may be decreased among HIV-infected children.

At least two mechanisms may account for the higher proportions of nonreactivity to tuberculin and of negative skin reaction in group 2 compared with group 3. First, some of the children who were HIV-antibody-negative at 15 months of age may nonetheless have been HIV-infected. In group 2, seven children alive as of September 30, 1991, had at least two signs of the WHO clinical definition of pediatric AIDS but were persistently HIV-antibody negative since the age of 12 months. For six of the seven children, results of the skin tests performed at 6 months of age were available: two had total tuberculin nonreactivity, two had a negative skin test, and two had a normal skin test. Second, circulating inhibitors of lymphocyte functions or soluble factors already identified in viral infections (6), including HIV infection among adults (7), could be transmitted from mother to child and could impair the cellular immunity of uninfected children born to HIV-positive mothers.

The differences in response to BCG between groups 2 and 3 have important practical implications. Uninfected children born to HIV-antibody-positive mothers could be at higher risk for acquiring TB because their mothers are more likely to reactivate a latent Mycobacterium tuberculosis infection. For this cohort of children in Rwanda, five HIV-positive mothers previously had been diagnosed with active TB, including one during pregnancy and four during the first 15 months postpartum. Three were mothers of children in group 1 and two of children in group 2.

The findings in this report support the continued practice of vaccinating asymptomatic infants in Africa with BCG for at least three reasons (1). First, because HIV-infected children are usually asymptomatic at birth, vaccinating these newborns with BCG appears to be a safe practice. Second, because side effects occur infrequently in infants after BCG vaccination during the neonatal period, mothers are likely to adhere to the sequence of vaccinations scheduled during infancy. Third, vaccinating HIV-infected infants with BCG could also provide cross-protection against atypical mycobacteria, an important cause of morbidity and mortality among AIDS patients (8).

References

1. World Health Organization. Expanded Programme on Immunization: Global Advisory Group. Wkly Epidemiol Rec 1990;65:5-11.

2. Lepage P, Dabis F, Hitimana DG, et al. Perinatal transmission of HIV-1: lack of impact of maternal HIV infection on characteristics of livebirths and on neonatal mortality in Kigali, Rwanda. AIDS 1991;5:295-300.

3. Lallemant-Le Coeur S, Lallemant M, Cheynier D, Nzingoula S, Drucker J, Larouze B. Bacillus Calmette-Guerin immunization in infants born to HIV-1-seropositive mothers. AIDS 1991;5:195-9.

4. Colebunders RL, Lebughe I, Musampu M, Pauwels P, Francis H, Ryder R. BCG cold abscesses are unrelated to HIV infection. JAMA 1988;259:352.

5. CDC. Tuberculin reactions in apparently healthy HIV-seropositive and HIV-seronegative women--Uganda. MMWR 1990;39:638-9,645-6.

6. Kantor FS. Infection, anergy and cell mediated immunity. N Engl J Med 1975;292:629-33.

7. Laurence J, Gottlieb AB, Kunkel HG. Soluble suppressor factors in patients with acquired immune deficiency syndrome and its prodrome. J Clin Invest 1983;72:2072-81.

8. Kallenius G, Hoffner SE, Svenson SB. Does vaccination with bacille Calmette-Guerin protect against AIDS? Rev Infect Dis 1989;11:349-51.

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