Repeated tuberculin testing in patients with active pulmonary tuberculosis.

OBJECTIVE: The proportion of tuberculin reactors in a population and the intensity of tuberculin reactions have been shown to increase with increasing exposure to mycobacterial infection, eg, repeated BCG immunization. These observations suggested that tuberculin reactivity would become uniformly high in individuals with a high mycobacterial load who did not have a known cause of anergy. Since tuberculin reactivity has been measured to evaluate the possible genetic regulation of responses to mycobacteria in humans, it is important to study its behavior under conditions of ongoing, maximal exposure to mycobacteria. In the present study, we determined the mean size of tuberculin reactivity in BCG-immunized and unimmunized patients with pulmonary tuberculosis of recent onset, and the stability of tuberculin reactions during and after treatment of pulmonary tuberculosis. METHOD: Serial tuberculin testing was performed on patients with newly diagnosed active pulmonary tuberculosis diagnosed over a period of 2 years at the National Institute for Respiratory Diseases in Santiago, Chile. The first tuberculin test was performed at the time of diagnosis in 58 patients. Repeated tuberculin testing was performed 2 weeks later in 15 patients with initial reaction sizes < 15 mm. Four additional tuberculin tests were performed, one each at 3-months intervals in 42 patients regardless of the size of the initial tuberculin reaction. RESULTS: Tuberculin reactions at entry had a unimodal distribution in patients both with and without BCG scars (14.8 +/- 5.0 mm and 16.5 +/- 5.2 mm, respectively). A second tuberculin test in patients with initial reaction sizes < 15 mm showed a moderate, statistically significant increase in the mean reaction size (PPD1: 10.1 +/- 3.2 mm; PPD2: 11.9 +/- 4.8 mm). Repeated tuberculin testing over 1 year revealed no significant changes in reaction size. The mean reaction sizes were 15.8 +/- 5.0 mm at entry, 15.5 +/- 5.4 mm at 3 months, 17.2 +/- 5.2 mm at 6 months, 17.0 +/- 5.1 mm at 9 months, and 16.7 +/- 54 mm at 12 months. The standard deviation of a random observation within patients was 5.3 mm. The largest variations due to increased reactivity after 6 months of treatment were observed in patients with reaction < 15 mm at entry compared with hyperergic patients, and in BCG-immunized patients compared to unimmunized patients. CONCLUSIONS: In the presence of an ongoing mycobacterial infection, patients without anergizing conditions express a tuberculin reactivity that is relatively constant during and after treatment of pulmonary tuberculosis. The size and stability of the reactions seem to be determined by individual conditions that include the tuberculin reactivity at the time of diagnosis and the BCG immunization status.

Booster effect of tuberculin testing in healthy 6-year-old school children vaccinated with Bacillus Calmette-Guérin at birth in Santiago, Chile.

In order to determine whether tuberculin testing caused a booster effect in children vaccinated with Bacillus Calmette-Guérin (BCG) at birth, we studied forty 6-year-olds by repeat tuberculin testing 2 weeks later on the contralateral forearm. All children were healthy and had no known exposure to tuberculosis. None of the children had a history of mycobacteriosis other than tuberculosis. The mean induration was 2.3 +/- 1.8 mm for the first tuberculin reaction and 7.6 +/- 3.3 mm for the second tuberculin reaction (P less than 0.005). Four children had positive reactions (greater than or equal to 10 mm) to the first purified protein derivative test; 18 children were positive upon retesting. Eleven of these latter children had increases of at least 6 mm from reactions less than 10 mm to greater than or equal to 10 mm. The size of the BCG scar was significantly correlated to the size of both the first and second purified protein derivative reactions (P less than 0.01), suggesting that the increased reactivity upon retesting was a consequence of sensitization induced by BCG vaccination 6 years earlier. All children remained healthy after this study was completed. Retesting of tuberculin reactivity within 2 weeks in BCG-vaccinated children with reactions less than 10 mm will produce reactions greater than 10 mm in some healthy children who may not require antituberculosis treatment.

Effect of human newborn BCG immunization on monocyte viability and function at 3 months of age.

SETTING: Immune response induced by BCG vaccination seems to reflect the development of T-cell immunity and monocyte activation. Participants were recruited from a large prospective study in infants from a suburb in Santiago, Chile. OBJECTIVE: To determine whether newborn BCG immunization changes the innate ability of cultured monocyte-macrophages to ingest and kill virulent mycobacteria in the absence of lymphocytes. DESIGN: The study population consisted of 15 three-month-old, tuberculin-positive infants immunized with BCG (Japanese) at birth, 13 randomly-selected, age-matched tuberculin-nonreactive infants in whom BCG immunization was postponed until one year of age, and five BCG-immunized, tuberculin-reactive adults. Adherent cells were cultured for 48 h. Monocyte-macrophage viability and number and viability of intracellular Mycobacterium tuberculosis bacilli were assessed after an additional 2 h and 4 and 7 days of incubation. RESULTS: There was no difference in the mean number of adherent cells present after 48 h among the three study groups. Adherent cells from BCG-immunized infants and adults had a significantly higher viability after 7 days in culture than adherent cells from non-immunized infants. The percentage of cells ingesting M. tuberculosis and the number of bacilli per cell after 2 h and 4 days was significantly higher in immunized infants and adults than in non-immunized infants. However, there was no evidence for increased killing of mycobacteria by cells from immunized infants and adults. CONCLUSION: These results suggest that BCG vaccination increases monocyte viability and the uptake of M. tuberculosis without enhancing the ability to kill ingested M. tuberculosis in the absence of lymphocytes.

Case-control study of the efficacy of BCG immunization against pulmonary tuberculosis in young adults in Santiago, Chile.

We performed a case-control study of the efficacy of BCG immunization against pulmonary tuberculosis in 15- to 35-year-old Chilean patients born during a period when BCG coverage was incomplete. Our aims were to determine BCG efficacy against pulmonary tuberculosis in young adults, to determine if repeated BCG immunization increased its protective effect, and to determine factors that could explain the failure of BCG immunization in patients with tuberculosis. We studied 68 patients who had pulmonary tuberculosis based on positive AFB in at least 1 of 2 sputum smears, a positive confirmatory culture and compatible chest roentgenogram abnormalities. The control group were 188 individuals without pulmonary tuberculosis seeking medical care for other ailments. The percentage of non-immunized individuals was 13.2 among patients with tuberculosis and 12.2 among controls. The vaccine efficacy calculated from these data was 10%. There was no difference in the percentage of individuals with 1, 2 and 3 BCG scars between tuberculosis patients and controls. The number and percent of individuals exposed to tuberculosis among BCG-immunized and non-immunized tuberculosis patients and controls were similar. No significant differences between BCG-immunized and non-immunized individuals were detected in tuberculosis patients or in the control group. However, tuberculosis patients as a group had significantly lower weight, education level, employment rate and family income than controls. These observations suggest that the development of pulmonary tuberculosis in BCG-immunized young adults is favored by the presence of genetic and/or acquired predisposing factors capable of overriding protective immunity induced by BCG vaccination.

The influence of Calmette-Guérin bacillus immunization on the booster effect of tuberculin testing in healthy young adults.

The booster or enhancement effect of repeated tuberculin skin testing in Calmette-Guérin bacillus (BCG)-vaccinated young adults was studied in 208 first-year medical, nursing, and medical technology students in Santiago, Chile, where BCG vaccine is usually administered at birth and at 6 and 14 yr of age. Thirty-three students had no BCG scar, 62 had one scar, 71 had two scars, and 42 had three scars. The mean age for each group was 19 yr. All students were healthy and had no known exposure to tuberculosis or history of tuberculosis or other mycobacterioses. The size in millimeters of induration of the first tuberculin reaction (PPD1) was clearly correlated with the number of BCG scars: 2.3 +/- 4.6 for no scars; 6.7 +/- 6.7 for one scar; 10.9 +/- 5.9 for two scars, and 13.2 +/- 5.3 for three scars. The second tuberculin reaction (PPD2), performed 2 wk later on the contralateral forearm, showed a marked increase in reactivity. The increase in reaction size was most evident in students who had BCG scars but who were initially PPD negative (less than 10 mm). Smaller increases were observed in students without BCG scars, and also in those who had BCG scars but who were initially tuberculin positive (greater than or equal to 10 mm). The persistence of the booster effect was evaluated by performing PPD3 1 yr later. PPD1-negative students with BCG scars maintained the increased level of reactivity to PPD2 after 1 yr. An immunizing effect of tuberculin testing was suggested in 11 nonimmunized students who were initially PPD negative.(ABSTRACT TRUNCATED AT 250 WORDS)

The influence of BCG immunization on tuberculin reactivity in healthy Chilean women in the third trimester of pregnancy.

SETTING: Tuberculin testing is an accepted method for screening pregnant women for tuberculosis. The interpretation of tuberculin reactivity in bacillus Calmette-Guerin (BCG)-immunized pregnant women is still in debate. OBJECTIVE: Four related issues were addressed: (1) The effect of pregnancy on tuberculin reactivity; (2) the effect of age differential on tuberculin reactivity; (3) the effect of repeated immunization with BCG; and (4) the risk of developing tuberculosis during pregnancy or a 3-year post-partum period. DESIGN: We performed tuberculin testing in 840 healthy Chilean women in the 32nd to 34th week of pregnancy; 807 had been immunized with 1 or more doses of BCG. There were 3 age groups: 177 were < or = 19 years old, 534 were 20-29 years old, and 129 were > or = 30 years old. All women in the study were followed at least 3 years post-partum. RESULTS: Women < or = 19 years old and non-pregnant women of similar age studied in the same geographical area had a similar distribution of the size of tuberculin reactions. Over 50% of all BCG-immunized women in each group had tuberculin reactions > or = 10 mm. A differential effect of different doses of BCG was significant only in 20- to 29-year-old women. None of the women in this study developed tuberculosis during pregnancy or a 3-year post-partum observation period. CONCLUSIONS: Healthy, BCG-immunized pregnant women may have positive tuberculin reactions without having an increased risk for tuberculosis. The incidence of tuberculosis and the BCG immunization status need to be considered in the development of policy recommendations for diagnosis and treatment of Mycobacterium tuberculosis infection in pregnant women.

Tuberculin reactivity after newborn BCG immunization in mono- and dizygotic twins.

SETTING: Studies showing significantly higher concordance of tuberculosis among monozygotic twins than dizygotic twins have provided support for genetically determined susceptibility to tuberculosis. OBJECTIVE: We wished to explore whether the development of delayed type hypersensitivity to tuberculin after newborn BCG immunization of twins suggested genetic regulation of the response to BCG in humans. DESIGN: Our study population consisted of 17 monozygotic twin pairs, 18 dizygotic twin pairs, and 64 single infants 3-34 months of age from Santiago, Chile. All had a BCG scar and were tuberculin tested by one trained nurse. RESULTS: The mean birth weight of both groups of twins was significantly lower than that of singletons and the percentage of individuals who failed to respond to tuberculin was approximately twice as high in twins as in singletons. After adjustment for birth weight and age by regression analysis, it was found that the distribution of tuberculin reactivity in both monozygotic and dizygotic twins was not significantly different from that of singletons. Both twin pair correlations is adjusted tuberculin reactivity were significantly greater than zero (P < 0.01) and led to a heritability estimate of 0.28. However, the monozygotic twin correlation was not significantly larger than the dizygotic twin correlation so that heritability is poorly estimated. CONCLUSION: These results are consistent with a genetic regulation of the response to newborn BCG immunization in humans by a mechanism capable of producing similar responses in identical and nonidentical twins alike.

Tuberculin reactivity in families of infants who failed to develop tuberculin reactivity after BCG immunization at birth.

SETTING: Some infants immunized with BCG in the newborn period fail to develop any measurable tuberculin reactivity despite a local reaction at the site of immunization. OBJECTIVE: We wished to determine the possibility of a genetic regulation of this phenomenon by comparing the tuberculin reactivity of BCG-immunized parents and siblings of infants who failed to respond to BCG, and of infants who developed tuberculin reactivity after immunization. DESIGN: We studied 65 parents and siblings of 33 nonresponder infants, and 35 parents and siblings of 14 infants who had developed tuberculin reactivity. Tuberculin reactivity was analyzed by multiple regression analysis considering the BCG immunization status of each individual, and the 2 groups were compared by analysis of covariance. RESULTS: 96 of these family members had one or more BCG scars. The percentages of tuberculin reactors and non-reactors among BCG-immunized family members of both index infant groups were not significantly different. CONCLUSION: These observations suggest that maturational differences among newborns, rather than genetic regulation, account for the lack of development of cellular immunity against tuberculin after BCG immunization in some infants.

Evaluation of tuberculin reactivity in BCG-immunized siblings.

The purpose of the present study was to determine in BCG-immunized sibships < or = 14 yr of age whether the correlations of intensity of tuberculin reactivity support a genetic regulation of the response to BCG immunization. The study population consisted of 659 healthy children living in 265 households exposed to an adult with tuberculosis: 38 children did not have a BCG scar, 327 children had one BCG scar, and 294 had two BCG scars from vaccinations at birth and at 6 yr of age. There were 603 full siblings, 16 half-siblings, and 40 unrelated children. Tuberculin testing was performed by one trained nurse. Sibling correlations of the intensity of the tuberculin response were calculated after adjusting for various nongenetic covariates that could be important in predicting it. The sibling correlations were significant at the 1% significance level. There was no significant correlation of tuberculin reactivity among unrelated children in the same household. These results are consistent with genetic regulation of the development and persistence of tuberculin reactivity after BCG immunization.