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1 February 1994 | Volume 120 Issue 3 | Pages 190-198
Objectives: No consensus exists regarding the definition and interpretation of a significant boosting reaction after sequential tuberculin testing. The booster phenomenon is thought to represent remote tuberculous infection where tuberculin reactivity has waned, but it has also been described among persons with previous exposure to other mycobacteria or bacille Calmette–Guérin (BCG) vaccine. We studied the factors affecting the booster phenomenon among Canadian-born young adults to determine the definition that would maximize sensitivity and specificity of a positive booster reaction in these persons.
Design: Point-prevalence survey of initial tuberculin reactions and response to repeated tuberculin testing after 1 to 4 weeks.
Setting: Community-based study of all students entering health professional training programs at six post-secondary institutions.
Measurements: In 1989, 1990, and 1991, students completed self-administered questionnaires, underwent two-step tuberculin testing with purified protein derivative-tuberculin (PPd-T), and had their childhood BCG vaccination status verified. In 1991, students were also tested with purified protein derivative-Battey (PPd-B) (for Mycobacterium intracellulare).
Results: Overall, 74 students (5.2%) had positive booster reactions, which were significantly associated with older age (P < 0.001), larger initial tuberculin reactions (P < 0.001), previous BCG vaccination (P < 0.001), older age when vaccinated (P < 0.02), longer interval from vaccination to testing (P < 0.01), and sensitivity to PPd-B (P < 0.001). Boosting was not associated with the number of BCG vaccinations, sex, or risk factors for tuberculous infection. The pattern, mean, and mode of the frequency distributions of booster reactions among those with BCG vaccination and sensitivity to PPd-B were similar to those with assumed tuberculous infection.
Conclusions: In young adults, booster reactions due to previous tuberculous infection are uncommon and cannot be distinguished from false-positive reactions due to past exposure to other mycobacteria.
Two-step tuberculin testing should increase sensitivity by detecting those with remote tuberculous infection but may also diminish specificity because the booster phenomenon has been associated with previous BCG vaccination [12-16] or sensitization with atypical mycobacteria [6, 17, 18]. Among young adults, who include most new hospital employees and have a low prevalence of tuberculous infection [6-8], it is unclear whether a significant booster reaction indicates remote tuberculous infection. Similarly, the risk for tuberculosis development in a young adult with a nonsignificant tuberculin reaction but a positive booster reaction is not known. Consequently, no consensus exists regarding the prognosis and definition of a significant booster reaction [4-6, 11, 19].
Quebec is unique in North America because BCG vaccinations were given en masse from 1948 to 1980. Thus, approximately 50% to 60% of young adults have received BCG vaccination [20, 21]. Fewer than 5% of nonvaccinated young adults have significant reactions to tuberculin or to atypical mycobacterial antigens [22]. We wanted to evaluate the factors associated with booster reactions and to estimate the sensitivity and predictive value of different criteria for the booster reaction in these young adults.
In Quebec from 1948 until 1980, BCG vaccinations were given en masse. More than 100 000 vaccinations were given each year, with 50% to 60% of the population vaccinated, although coverage varied from 10% to 80% in health districts within greater Montreal [21]. Vaccination was given by the scarification method using vaccine manufactured by the Institut Armand Frappier (Laval, Quebec). Infants received 3 x 106 viable bacilli, and all other persons were given 5 x 106 bacilli [20]. More than 90% of recipients had significant tuberculin reactions when tested 6 to 8 weeks later [20]. Most were vaccinated in infancy, although 20% were vaccinated at primary school entry, and fewer than 10% were vaccinated at ages 10 to 16 years. All BCG vaccinations were recorded in vaccination booklets, which were given to each child, and at a central registry at the Institut Armand Frappier. These records are still readily accessible.
Participant Selection
The faculties of health sciences and the student health services of six post-secondary institutions in Montreal were contacted. All students entering health professional training programs in 1989, 1990, and 1991 were eligible, except those who were on leave or receiving immunosuppressive therapy. Those with previously documented positive tuberculin tests completed questionnaires, and their previous results were recorded. The results among foreign-born students, whose BCG vaccination status could not be verified, have been reported elsewhere [23]. This study was approved by an ethics committee of the Montreal Chest Hospital.
Data Collection
Before skin testing, students gave informed consent and completed self-administered questionnaires regarding demographic data, BCG vaccination, previous skin tests, and potential exposure to tuberculosis.
Using plastic disposable syringes and 27-gauge needles, 0.1 mL of 5 TU PPd-T (for Mycobacterium tuberculosis; Connaught Laboratories, Toronto, Canada) was injected intradermally on the volar aspect of the forearm, using the Mantoux technique. In 1991 only, students were also initially tested with 0.1 mL of purified protein derivative-Battey (PPd-B) (for M. intracellulare; Connaught Laboratories) on the volar aspect of the opposite forearm. After 48 to 72 hours, the maximal induration was defined using the ballpoint method [24], measured using machinists' calipers, and recorded in millimeters by one of four experienced readers. Those with reactions to the first test (PPd-T1) of 10 mm or more were not retested. Those with reactions to PPd-T1 of less than 10 mm were retested 1 to 4 weeks later (PPd-T2) on the opposite forearm using the same techniques for testing and reading. Bacille Calmette–Guérin vaccination was verified from childhood vaccination booklets, through the registry of the Institut Armand Frappier, or both. The accuracy of this information was previously verified [22].
All students with PPd-T1 or PPd-T2 reactions of 10 mm or more were referred to the Montreal Chest Hospital for chest roentgenogram and further evaluation. Roentgenogram reports were reviewed and classified as consistent with previous tuberculous infection if there was mention of granulomata, hilar calcifications, or apical pleuroparenchymal scarring.
Data Analysis
Initial Tuberculin Reaction
For students who had initial dual testing with PPd-T and PPd-B in 1991, the results of the reactions to the two antigens were adjusted as described below. This adjustment was based on evidence that U.S. military recruits with simultaneous reactions to PPd-B that were larger than to PPd-T had a low risk for tuberculosis, unless the reaction to PPd-T was 12 mm or more [25].
If PPd-T1 was less than PPd-B and PPd-T1 was less than 12 mm, then the reaction to PPd-T1 was assumed to represent cross-reactivity and the result was adjusted to zero; if PPd-T1 was 12 mm or more, no adjustment was made, regardless of size of PPd-B reaction; if PPd-T1 was equal to or greater than PPd-B, then PPd-B was assumed to represent cross-reactivity and the result was adjusted to zero.
PPd-T1 was considered positive if the reaction measured 10 mm or more (for students in 1991, after adjustment as above), and PPd-B was considered positive if the reaction measured 5 mm or more.
Booster Reaction
A dichotomous outcome was defined as positive if PPd-T2 was 10 mm or more and measured at least 6 mm more than PPd-T1 [5, 6, 14, 15, 26, 27].
Boosting Effect
A continuous outcome measured in millimeters was defined as PPd-T2 minus PPd-T1. This was used to analyze the biologic determinants of boosting and to examine the frequency distribution of change in reaction size associated with different factors.
Using these definitions, associations were tested for statistical significance using the chi-square test for categorical and the Student t-test for continuous independent variables [28]. All data were analyzed using a personal computer and SAS (SAS Institute, Cary, North Carolina) and BMDP software (BMDP, Statistical Software, Los Angeles, California) for logistic regression. A P value less than 0.05 was accepted as evidence of statistical significance [28]. Confidence intervals (95%) for proportions were calculated as suggested by Colton [28]; adjusted odds ratios were calculated from logistic regression as suggested by Kleinbaum and Kupper [29]. Sensitivity, specificity, and positive predictive values were calculated as suggested by Sackett [30]; measures of agreement were calculated according to methods described by Feinstein [31].
Of 2399 eligible students, 1961 (81.7%) completed the two-step testing protocol (Table 1). This report was confined to the 1542 Canadian-born students whose BCG vaccination status could be verified (from vaccination booklets for 1004 participants and from the records of the Institut Armand Frappier for 538 participants). Records of 332 students who had vaccination booklets were also traced through the central registry to verify accuracy and concordance of these two sources. Agreement between the two sources was 84% (ARTICLE
The Booster Effect in Two-Step Tuberculin Testing among Young Adults in Montreal
The resurgence of tuberculosis [1], and the emergence of multiple-drug-resistant strains of bacteria [2] in North America has heightened awareness of the risks for nosocomial transmission of tuberculosis. Periodic tuberculin testing has been recommended for health care personnel who are likely to be exposed [1, 3, 4] after initial two-step testing [1, 3-6]. Two-step tuberculin testing has been recommended because a single tuberculin test may elicit little response yet stimulate an anamnestic immune response so that a second test, even when done as soon as 1 week later, may elicit a much larger, or boosted, response [5, 7, 8]. This booster phenomenon is thought to represent remote tuberculous infection among elderly persons because it is more common with increasing age [6, 9, 10]. Among residents in Arkansas nursing homes, those with a reaction to a second tuberculin test of 10 mm or more had the same risk for tuberculosis infection as did those with an initial tuberculin reaction of 10 mm or more [11].
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Bacille Calmette–Guéerin Vaccination
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Participants
statistic = 0.68). In all, 591 (38%) students had received BCG vaccination, of whom 64% were vaccinated only once in infancy, 24% once between the ages of 2 and 10 years (median, 6 years), and 12% twice, primarily in infancy and between the ages of 5 and 7 years. The mean (±SD) age of the participants was 21.4 ±4.1 years and 84% were female, reflecting the preponderance of female students in many health professional training programs.
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Skin Testing
Of the 1542 participants, 107 (6.6%) had positive reactions to PPd-T1, were referred for evaluation, and were not retested. Of the 440 students tested in 1991, 26 (5.9%) had reactions to PPd-B measuring 5 mm or more, and 7 (1.6%) had reactions measuring 10 mm or more.
Among the 1435 students who had a second test (PPd-T2), initial reactions to PPd-T1 had an important effect on boosting, as shown in Table 2. The proportion with positive booster reactions increased with larger size of initial reaction, as did the mean booster effect measured in millimeters. However, of the 74 students with a positive booster reaction, 49 (66%) had an initial reaction to PPd-T1 measuring 0 mm.
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After correction for cross-reactivity to PPd-T1, BCG vaccination did not have any significant effect on reactions to PPd-B. Of the 591 students vaccinated with BCG, 84 (14.2%) had positive PPd-T1 reactions, compared with 22 of the 951 students (2.3%) who were not vaccinated (chi-square test; P < 0.001). Among those vaccinated only once, 31 (8.1%) of the 382 students vaccinated with BCG in infancy had positive initial tuberculin reactions compared with 5 of 30 (17%) students vaccinated at ages 2 to 5 years and 29 of 112 (26%) students vaccinated at 6 years or older (Mantel-Haenszel chi-square test; P < 0.001). Of the 68 students vaccinated twice, 21 (31%) had positive initial reactions, compared with 34 (24%) of the 142 students vaccinated only once after infancy (P = 0.3).
Bacille Calmette–Guérin vaccination had a significant effect on the boosting phenomenon. Of the 507 students vaccinated with BCG who had a second tuberculin test (PPd-T2), 51 (10.1%) had a positive booster reaction, compared with 23 of 929 (2.5%) students who were not vaccinated (chi-square test; P < 0.001). In total, 75% of those who received BCG vaccination, compared with 95% of those who were not vaccinated, remained negative for tuberculin antibodies after two-step testing (chi-square test; P < 0.001). As seen in Figure 1, BCG vaccination appeared to affect the booster reaction at all size ranges, including reactions measuring more than 15 mm.
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Sensitivity to PPd-B
Sensitivity to PPd-B was associated with smaller simultaneous reactions to PPd-T1 (therefore considered false-positive PPd-T1 reactions) in 3 of 15 (20%) students with reactions to PPd-T1 of 5 to 9 mm but in only 1 of 24 (4%) students with reactions to PPd-T1 measuring 10 or more mm. Despite this, sensitivity to PPd-B was significantly associated with boosting. Of the 386 students with no reaction to PPd-B, 2.9% had a booster reaction compared with 10.5% of those with a reaction to PPd-B of 5 to 9 mm and 27.3% of those with reaction of 10+ mm (Mantel-Haenzsel chi-square test; P < 0.001). As shown in Figure 2, the booster effect (expressed in millimeters) was larger among those with greater reactions to PPd-B (analysis of variance; P < 0.001). As shown in Figure 3, the prevalence of booster effects of all sizes, from 4 to 15+ mm, was greater among those with any reaction to PPd-B.
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Sex was not significantly associated with initial or boosting reactions, although the power to detect any such association was limited by the relatively small number of male participants. As shown in Table 3, older age was significantly associated with sensitivity to PPd-B (P < 0.01), and the prevalence of initial and booster reactions was significant in the students who were not vaccinated and in those vaccinated in infancy. Among those vaccinated after infancy, a shorter interval may have occurred because of vaccination at an older age (tending to increase tuberculin reactivity) or because of younger age when tested (tending to reduce tuberculin reactivity). As shown in Table 3, among those vaccinated after infancy, the percentage with a positive booster reaction increased with greater interval up to 25 years, although differences were not significant because there were few students in three of the four categories.
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Of the 107 students with positive initial tuberculin reactions, 74 had a chest roentgenogram at the Montreal Chest Hospital. Ten (14%) of these students had abnormalities consistent with previous tuberculous infection. Of 88 students with PPd-T2 reactions measuring 10 or more mm, 61 had a chest roentgenogram and 6 (10%) of these had radiographic evidence of previous tuberculous infection (P = 0.4). No student had active tuberculosis. Information was not available for 60 students.
We used logistic regression to obtain an adjusted estimate of the effect of each of these factors. As shown in Table 5, initial tuberculin reactions to PPd-B and BCG vaccination (particularly if students were vaccinated after infancy) were significantly associated with booster reaction. Sex, age, previous skin tests, number of BCG vaccinations, and interval from vaccination to testing in the study were not significantly associated with the booster phenomenon.
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10 mm [9, 11, 17, 26]; boosting by this definition is associated with increasing age [9, 26] and with the same risk for tuberculosis as initial tuberculin reactions of 10 mm or more among residents of nursing homes [11]. The second is PPd-T2 10 mm and PPd-T2 minus PPd-T1 6 mm; this is the most commonly used definition [5, 6, 14, 15, 26, 27]. The additional criterion of 6 mm was suggested to account for random variation in tuberculin test readings of 2 to 3 mm [6]. A third definition is PPd-T2 minus PPd-T1 12 mm; this was suggested because the risk for tuberculosis infection was highest among residents of Arkansas nursing homes who had increases of 12 mm or more on periodic retesting [32]. The fourth definition is PPd-T2 15 mm, which was adopted in the most recent ATS statement [19, 33]. As shown in Table 6, use of these increasingly stringent criteria to define a boosted reaction as indicating tuberculous infection in our study participants resulted in diminished sensitivity and no improvement in the positive predictive value. In the calculations for Table 6, we assumed that the least stringent definition, a PPd-T2 reaction measuring 10 mm or more, had a sensitivity of 100% (that is, that all those with tuberculous infection would manifest at least this reaction). In addition, we assumed that those with a significant booster reaction but no sensitivity to PPd-B and no history of BCG vaccination actually were infected with tuberculosis.
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Discussion
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These results should be of interest to North American health centers where initial two-step testing is conducted. The prevalence of significant initial tuberculin reactions was low among students who were not vaccinated, which allowed identification and analysis of false-positive boosting reactions. Bacille Calmette–Guérin vaccination was verified using childhood vaccination records from two independent sources, which should have been more reliable than the presence of postvaccinal scars used in previous studies [13-16] because these may be absent in 18% to 25% [14, 34] or in as many as 78% to 83% [13, 16] of students vaccinated with BCG. Selection bias should have been minimized because a high proportion of those eligible participated and because BCG vaccination was given based on decisions of regional public health authorities rather than on individual risk factors.
The primary limitation of this study was potential misclassification of BCG vaccination. However, this should have been minimal because information regarding BCG vaccination was available from two sources, including childhood vaccination booklets in 40% and a central registry in the rest. Agreement between these two sources was substantial [31]. In a separate study to assess the consistency of the registry records, excellent agreement between two separate verifications of the same 304 records was obtained [22]. The generalizability of these findings may be limited because the effect of BCG vaccination on tuberculin reactions may vary, depending on the method of administration [35] or the vaccine manufacturer [36]. However, we previously found that the effect of BCG vaccine manufactured by the Institut Armand Frappier and administered by the scarification method on initial tuberculin reactivity is similar to the effect of BCG from different manufacturers and administered by different methods reported in other studies [13-16, 22, 36].
A second potential limitation was that previous sensitization to atypical mycobacterial antigens was estimated from reactions to PPd-B only. However, in Montreal schoolchildren who had testing with multiple mycobacterial antigens [37] and in patients with disease due to different nontuberculous mycobacteria [38], reactions to PPd-B were the most prevalent. Therefore, sensitivity to PPd-B appears to be a reasonable marker of sensitization to all atypical mycobacterial antigens [38].
It is unlikely that anergy was an important cause of false-negative tests. This was a community-based study of young, healthy students, and those with potential immunosuppression (resulting from use of systemic corticosteroids, for example) were excluded. It is also unlikely that unrecognized human immunodeficiency virus (HIV) infection played an important role, because more than 80% of the population were young women, among whom HIV seroprevalence was less than 0.2% in a Montreal area survey conducted in 1989 [39].
False-positive Booster Reactions
Bacille Calmette–Guérin vaccination was the most important cause of booster reactions. Five previous studies examined the effect of BCG vaccination on boosting. In the first [12], mean tuberculin reactions were larger 4 years after BCG vaccination if there had been intercurrent annual tuberculin testing. In the other four studies [13-16], 12% to 30% of children and adolescents who were vaccinated 3 to 10 years earlier had positive booster reactions. In these studies, vaccinal scars were recorded, but in only one study were these scars associated with boosting [15]. Nonvaccinated subjects were not included in any of these studies, and thus the effect of BCG could not be distinguished from that of other mycobacterial infections. Among the foreign-born students tested, history of BCG vaccination was the most important factor associated with boosting, even among students from countries with the highest tuberculosis rates [23].
Similar to the effect on initial tuberculin reactivity [22, 36, 40], BCG vaccination received in infancy had little effect on the booster phenomenon, except in those who reported a tuberculin test within the previous 4 years. The prevalence of initial and booster reactions increased with longer intervals since vaccination, reflecting the greater likelihood, among those who were older, of sensitization with additional mycobacterial antigens. The appearance of booster reactions only after a third, or even a fourth, sequential tuberculin test among the elderly, particularly those who are especially old [26, 27], has been attributed to their weaker immunity and need for greater antigenic stimulation [27]. The immune response after BCG vaccination in infancy is weaker [41] and subject to greater waning [22, 40]. Therefore, the additional antigenic stimulus of a third sequential tuberculin test may be necessary to induce a significant response. However, inferences regarding the effect of a third tuberculin test are limited because this was not systematically examined in our study.
In the southern United States, sensitivity to atypical mycobacterial antigens is common [25] and is considered to be an important cause of the booster phenomenon [6, 17, 18]. Although only 5% of the students were sensitive to PPd-B, this sensitivity was an important cause of false-positive boosting reactions of all sizes. Those who were vaccinated with BCG and sensitive to PPd-B had more frequent and larger booster reactions than did any other group, differences that were statistically significant despite their small numbers.
Definitions and Prognosis of Boosting Reactions
The current definition of a significant initial tuberculin test [19] is based on longitudinal data regarding the relation of risk for tuberculosis with size of reactions [25, 42, 43] and an understanding of the causes of false-positive reactions. The frequency distributions of true-positive reactions among those with tuberculous infection [44] are different from the pattern of false-positive reactions associated with BCG vaccination in infancy [22] or atypical mycobacterial infection [25]. The mean and mode of true-positive tuberculin reactions are greater than those of false-positive reactions, and thus use of more stringent criteria to define a significant tuberculin reaction [19] increases the positive predictive value, although with some reduction in the sensitivity of the test [30].
However, as shown in Table 6, application of increasingly stringent definitions of a positive booster reaction in our study participants resulted in reduced sensitivity without improvement in the positive predictive value. This is because the mean, mode, and frequency distributions of false-positive boosting reactions associated with BCG vaccination, or sensitivity to PPd-B, were similar to assumed true-positive boosting reactions, as shown in Figure 1 and Figure 3.
Our study provides data to show that the booster phenomenon is a nonspecific manifestation of all previous mycobacterial sensitization but only limited data regarding the clinical significance of booster reactions in young adults. Risk factors for tuberculous infection were significantly associated with initial tuberculin reactions but were not associated with boosting. Similarly, radiographic abnormalities consistent with previous tuberculous infection were more frequent in those with initial tuberculin reactions compared with those with boosted reactions. No data exist from longitudinal surveys of young adults with significant boosted reactions, but in longitudinal surveys among Danish schoolchildren [36], U.S. military recruits [25], and refugees from southeast Asia [43], incidence of active tuberculosis was very low among those with initial tuberculin reactions measuring less than 10 mm, unless a history of household contact, abnormal chest roentgenograms, or other risk factors were present. Therefore, young adults born in North America who have a positive boosted reaction after two-step tuberculin testing should not be considered to have tuberculous infection in the absence of other risk factors. Appendix Table 1
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Abbreviations
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PPd-B: purified protein derivative-Battey
PPd-T: purified protein derivative-tuberculin
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