The current value of tuberculin testing and BCG vaccination in school children

We have examined the value of routine tuberculin testing and BCG vaccination in Edinburgh school children from 1970 to 1983. Over 89,000 children were observed for a mean period of 7 years, during which 77 new cases of tuberculosis were notified in Caucasians. The average annual incidence of tuberculosis in the 65,692 children receiving BCG vaccination at school was 7/10(5), significantly less than the 19/10(5) estimated in 12,987 Heaf negative children who missed BCG vaccination, and the 41/10(5) in 5,308 tuberculin positive children (P less than 0.001). The efficacy of BCG vaccination in this study exceeded 60%. The 5,308 tuberculin positive children were offered chest radiographs with an initial yield (new cases of tuberculosis detected/radiographs taken) of 1/555 for Heaf grade II children, 1/75 for grade III, and 1/25 for grade IV (P less than 0.001). During the period of this study approximately 700 BCG vaccinations were necessary to prevent one new case of tuberculosis and this represents considerably greater benefit than in England and Wales during the same period. There may be a case for continuing the schools' BCG programme in Scotland for a number of years longer than in England and Wales. A national BCG survey for Scotland would be valuable.     

Efficacy of the BCG revaccination programme in a cohort given BCG vaccination at birth in Hong Kong.

SETTING: Revaccination of tuberculin-negative school-children is a regular practice in Hong Kong. OBJECTIVE: To assess the efficacy of BCG revaccination guided by tuberculin skin testing. METHOD: A cohort of 303,692 children vaccinated at birth was followed through the tuberculosis notification register for the development of active disease. The percentage of cohort who participated in the BCG revaccination program during primary school was estimated from the vaccination statistics of the Hong Kong Department of Health. The BCG revaccination history of identified cases was ascertained through vaccination cards and clinic records. RESULTS: A total of 85.2% of the cohort participated in the BCG revaccination programme; 79.7% of the participants were tuberculin-negative and revaccinated; 343 developed tuberculosis after the age of 11; 302 were among the participants in the programme while 41 were not. The tuberculosis incidence was 16.5 and 12.9 per 100,000 person-years for participants and non-participants, respectively (RR 1.28, 95%CI 0.92-1.77). Among the participants, tuberculosis incidence was 12.5 and 32.0/100,000 person-years, respectively, for the tuberculin-negative/BCG revaccinated group and the tuberculin-positive/non-revaccinated group (RR 0.39, 95%CI 0.31-0.49). CONCLUSION: This study failed to demonstrate any significant difference in the incidence rates of tuberculosis among participants and non-participants in a school BCG revaccination programme. The increased risk for tuberculosis in the tuberculin-positive group does not support the use of the tuberculin testing for detection of immunity conferred by neonatal BCG vaccination.     

The effect of BCG vaccination on tuberculin reactivity and the booster effect among hospital employees

BACKGROUND: We estimated the effect of remote BCG vaccination on tuberculin reactivity and the booster effect among hospital employees. METHODS: Cross-sectional survey at a university hospital. All personnel employed during a 24-month period were included in the study. Employees were administered 2-step tuberculin testing, and BCG vaccination scars were verified. RESULTS: Of 665 hospital employees studied, 239 (36%) had been vaccinated with BCG in childhood. Significant tuberculin reactions (> or =5 mm) were more frequent among BCG-vaccinated (60%) than among nonvaccinated (29%) employees (odds ratio [OR], 3.6; 95% confidence interval [CI], 2.6-5.2). The predictive value of tuberculosis infection increased with increasing reaction size and greater age (from 37% in subjects 30 years or younger with indurations > or =5 mm to 100% in subjects 50 years or older with indurations > or =15 mm). Among 374 employees with a negative tuberculin test reaction who underwent a second test, 39 (43%) of 91 vaccinated subjects had a positive booster reaction in contrast to 51 (22%) of 232 nonvaccinated subjects (OR, 3.4; 95% CI, 2-5.7). Neither different size criteria nor different definitions of the booster effect had an impact on the predictive value of tuberculosis infection. CONCLUSIONS: Remote BCG vaccination largely influences the tuberculin reaction and the boosting phenomenon among hospital employees. The interpretation of the results of 2-step tuberculin testing in a BCG-vaccinated subject must take into account age, size of the reaction, and local prevalence of tuberculosis infection. No single criterion, however, can accurately separate reactions caused by true infection from those caused by BCG vaccination.     

The effect of neonatal bacille Calmette-Guérin vaccination on purified protein derivative skin test results in Canadian aboriginal children

BACKGROUND: The effect that neonatal bacille Calmette-Guérin (BCG) vaccination has on tuberculin skin test (TST) results is not well evaluated in preschool children. METHODS: This was a retrospective cohort study of TST results in aboriginal children in Saskatchewan reserve communities. Records from the centralized provincial tuberculosis program were searched for aboriginal children aged 0 to 4 years during the time period 1991 to 1999. Only the first TST result reported as part of infant and preschool screening programs was considered. Children with active tuberculosis and those evaluated as part of a contact-tracing program were excluded. The BCG-vaccinated and unvaccinated groups were compared using wheal size cut points of 5 mm, 10 mm, and 15 mm. RESULTS: Data from 1,086 children with neonatal BCG vaccination and 1,867 unvaccinated children were analyzed. The rate of TST reactions was higher in vaccinated children at all ages, using a cut point of 5 mm. The rate of TST reactions was no different in vaccinated children >or= 1 year old when using a cut point of 15 mm. When using a cut point of 10 mm, the rate of TST reactions was higher at age 1 year but not different at age 4 years in the vaccinated children. CONCLUSION: The rate of TST reactions in preschool aboriginal children living on a reserve who have received neonatal BCG vaccination is affected by the cut point and age. The BCG vaccination status and age should therefore be considered when interpreting TST reactivity in the clinical assessment of aboriginal children participating in a tuberculosis control program.     

Coincident filarial, intestinal helminth, and mycobacterial infection: helminths fail to influence tuberculin reactivity, but BCG influences hookworm prevalence

The prevalence of helminth and tuberculosis infections is high in South India, whereas Bacille-Calmette-Guerin (BCG) vaccine efficacy is low. Our aim was to determine whether concurrent helminth infection alters the ability to mount a delayed-type hypersensitivity response to tuberculin. In a cross-sectional study in southern India, individuals 6-65 years of age were screened for intestinal helminths, circulating filarial antigenemia, tuberculin reactivity, active tuberculosis, and history of BCG vaccination; 54% were purified protein derivative (PPD) positive, 32% had intestinal helminth infection, 9% were circulating filarial antigen positive, and 0.5% had culture-confirmed active tuberculosis. Only age and BCG vaccination were significantly associated with PPD reactivity; however, BCG vaccination was associated with a lower prevalence of hookworm infection relative to those without prior BCG vaccination. Neither intestinal helminth infection nor filarial infection was associated with diminished frequencies of PPD positivity. Our findings suggest that preceding helminth infection does not influence significantly the delayed-type hypersensitivity response to tuberculin.     

The tuberculin skin test in relation to immunological in vitro reactions in BCG-vaccinated healthcare workers.

The aim was to study the tuberculin skin test in relation to immunological in vitro reactions in bacille Calmette-Guerin (BCG)-vaccinated healthcare workers. The present study was performed in Sweden, a country with a low incidence of tuberculosis, a high BCG vaccination efficacy and high tuberculin conversion rates. BCG-vaccinated healthcare workers (n=381) were tuberculin skin tested. From these, 11 subjects with negative tuberculin reactions (<6 mm) were matched for age and sex with 11 subjects with large positive reactions (> or = 15 mm). Lymphocyte transformation and the production of interferon-gamma (IFN-gamma) were analysed after stimulation in vitro of peripheral blood mononuclear cells with tuberculin purified protein derivative, heat-killed tubercle bacilli and a culture filtrate from tubercle bacilli. In the tuberculin-positive group the lymphocyte transformation response was 2-3 times larger, and IFN-gamma production was 7-10 times larger, than in the tuberculin-negative group (p<0.001). The present results suggest that a positive tuberculin skin test in bacille Calmette-Guerin-vaccinated subjects indicates a stronger immune response of the protective T-helper 1-type than does a negative test. In similar settings, the study supports the traditional practice of regarding the tuberculin skin test in bacille Calmette-Guerin-vaccinated subjects as an indicator of a protective immune response against tuberculosis.     

The persistence of tuberculin sensitivity following oral BCG vaccination in The Netherlands

Certain anomalies in the tuberculin test results in Netherlands schoolchildren in the late 1960s and in recruits a few years later are shown to have arisen from the persistence of tuberculin sensitivity in some of the 10 000 newborn children who were given oral BCG vaccine in the early 1950s. More than 90% of these oral BCG vaccinations were given in 1950 or 1951 in Amsterdam, Delft or Hilversum, but because of the absence of a scar or any record, individuals who were vaccinated cannot now be distinguished from the much larger numbers of unvaccinated subjects. The cohorts of Dutch children born in 1950 and 1951 showed excess positivity, compared with earlier and later cohorts, when tuberculin tested at different ages in adolescence and as army recruits, and this was especially noticeable among current residents in these three cities. It is estimated that less than 10% of those given oral BCG vaccine in the Netherlands in 1950 or 1951 showed positive reactions at ages 12 and 13, but about 20% did at age 16, and about 45% at age 18. A review of data on tuberculin sensitivity several years after intradermal BCG vaccination in the newborn or in young children suggests that sensitivity persists in only a relatively small proportion for a long period (in perhaps about 45% after 7 years and less after a longer period), unless boosted by intervening tuberculin tests. The present data on oral BCG vaccination in the newborn conform to the same pattern.(ABSTRACT TRUNCATED AT 250 WORDS)     

Long-term results of BCG vaccination in the southern United States

A controlled trial of Bacille Calmette Guerin (BCG) vaccination was conducted in 1950 among 64,136 residents of Muscogee County, Georgia, and Russell County, Alabama. Only 11% of the total study population is now estimated to have been infected with Mycobacterium tuberculosis. About half of the initial nonreactors to tuberculin were vaccinated. Throughout 14 years of observation, tuberculosis continued to develop more frequently among initial reactors than among those who were nonreactors at the start of the trial. Among the nonreactors, vaccination accounted for a reduction in tuberculosis of only 14%, meaning that the net reduction in the entire study population was less than 5%. The slight contribution made by vaccination was manifested almost entirely during the 1st 4 years of the trial. Moreover, BCG vaccination was least effective among groups most in need of protection, especially Blacks. Although tuberculosis appeared to be most common among persons with small amounts of subcutaneous fat and those in inadequate housing, there was no indication that either of these factors could account for the lack of effectiveness of BCG vaccination. It is concluded that the risk of tuberculosis among nonreactors is too low to justify the use of BCG in the US. To achieve a dramatic decline in tuberculosis morbidity, it is necessary to find ways to stop the continued development of tuberculosis among persons with old established infections.     

Causes of ineffectiveness of BCG vaccination and its impact on childhood tuberculosis

In the last few years BCG vaccination has covered 97% of the newborns, but in 45% of them this vaccination proves to be low effective since no more than 2- or 3-mm long postvaccination cicatrix disappears by the 2-nd or 3-d year of their lives. The reasons of a low efficacy of BCG vaccination include inadequate BCG vaccination techniques, incomplete administration of the inoculation dose, etc. Cases of M. tuberculosis infection in children ineffectively vaccinated with BCG are 3 times more than among those effectively vaccinated and having postvaccination cicatrix.     

The protective effect of BCG vaccination of the newborn against childhood tuberculosis in an African community

The latest controlled trial of BCG vaccination in southern India showed that two vaccines failed to confer protection against pulmonary tuberculosis. This result cast serious doubt on the effectiveness of BCG vaccination of the newborn, which is widely applied in developing countries. Therefore, WHO initiated a global research study to evaluate current programmes in developing countries. Part of this study was carried out in Lomé, Togo, in which child contacts of newly detected patients were followed up with clinical and radiological examinations. All observations were recorded according to a scoring system. Concomitant observations were made to verify the comparability of the vaccinated and unvaccinated children. Of the child contacts of 352 index cases, 1421 completed the examinations. The distribution of the final score made it possible to distinguish 175 children likely to suffer from tuberculosis: 113 among the 546 unvaccinated and 62 among the 875 vaccinated children. Significant incomparability was observed in respect of intensity of exposure: the vaccination coverage was relatively low, and the risk of disease relatively high, if a parent was the index case or the child shared the bedroom of the index case (which very often coincided). The other variables studied, including age and sex, turned out to be practically irrelevant as regards comparability. The estimate of the protective effect against all types of tuberculosis combined is 61.5%, which is slightly lower than suggested by the raw data (66%). The protective effect, however, appeared to increase considerably with severity of disease. In children of 5 years and older it was lower than in the younger children. Tuberculin testing failed to reveal any sensitivity induced by BCG in the vaccinated children. The distribution of the tuberculin reactions correlated poorly with the other diagnostic findings. Small reactions were only slightly more frequent in healthy than in sick children; only the very large reactions were associated with a higher risk of disease. This confirms that the tuberculin test is of very limited diagnostic value in young children.     

A study on estimating the natural TB infection prevalence in BCG vaccinated regions

The authors analysed the distribution of the sizes of tuberculin reaction of those who have not been BCG vaccinated. The result shows that the proportions of persons with certain tuberculin reactors, greater than or equal to 6mm to greater than or equal to 15mm, greater than or equal to 6mm to greater than or equal to 20mm and greater than or equal to 15mm to greater than or equal to 20mm are relatively stable. Comparing the tuberculin inoculation size in BCG vaccinated group with those of non vaccinated, it shows that the size of tuberculin reactions greater than or equal to 15mm might not be influenced by BCG vaccination. It seems that the number of reactors of greater than or equal to 15mm are able to be used to estimate the prevalence of natural TB infection in BCG vaccinated regions.     

Childhood tuberculosis in the State of Qatar: the effect of a limited expatriate screening programme on the incidence of tuberculosis.

OBJECTIVE: To determine incidence rates and the effectiveness of the expatriate screening programme on paediatric tuberculosis (TB) in the State of Qatar. METHOD: A state-wide, population-based, retrospective analysis of all cases of tuberculosis among children 0-14 years of age reported to the TB Unit of the Division of Public Health during 1983-1996. RESULTS: One hundred and forty-four children with tuberculous disease were identified, with a steadily declining incidence rate (rate of notification) from 11/100000 children (0-14 years) population in 1983 to 7/100000 in 1996. This decrease in the childhood TB case notification rate correlated with foreign-born children, older children and the implementation of expatriate screening in 1986. Diagnosis in 56% of children was made abroad or within 3 months of arrival from vacation and 30% within one year of arrival. Comparison of the three age groups (<5, 5-9 and 10-14 years) showed no significant difference with regard to nationality, sex, type of TB, radiological findings and screening. However older children were more likely to be symptomatic (P < 0.0001) and to have positive tuberculin skin test (TST) reactivity (P = 0.012), culture (P < 0.0001), and gastric aspirates (P = 0.018). CONCLUSION: Although there was a 36% decrease in paediatric TB incidence after the implementation of expatriate screening in 1986, Qatar has a high rate of paediatric tuberculosis. The policy of BCG vaccination at birth should be continued, and screening children at school entry and on return from vacation would be useful for further case identification.     

Tuberculosis epidemiology in six provinces of Vietnam after the introduction of the DOTS strategy.

SETTING: Six provinces in Vietnam where the DOTS strategy was introduced in 1989. OBJECTIVE: To assess the impact of improved tuberculosis (TB) control on TB epidemiology in Vietnam. METHODS: Data from the surveillance system in the period 1990-2003 were analysed to assess trends of notification rates and the mean ages of notified cases. Data from repeated tuberculin surveys in the period 1986-2002 were estimated to assess the prevalence of TB infection, the annual risk of infection and its trend using various cut-off points in those with and without bacille Calmette-Guérin (BCG) scar. RESULTS: Age-standardised notification rates in the period 1996-2003 declined significantly, by 2.6% to 5.9% per year, in five provinces. However, in four provinces notification rates in the age group 15-24 years increased significantly, by 4.5% to 13.6% per year, during this period. The mean age of newly diagnosed patients with smear-positive TB increased up to 1995 but decreased thereafter. The annual risk of TB infection showed a significant annual decrease (4.9% per year) in one province in surveys performed between 1986 and 1997, and in two provinces (6.6% and 4.7%) in surveys conducted between 1993 and 2002. CONCLUSION: These data suggest limited impact to date of the DOTS strategy in Vietnam.     

Tuberculin survey in the Eastern Province of Saudi Arabia

We present the results of the Mantoux test (5 units tuberculin) survey in the Eastern Province of Saudi Arabia, which was conducted as part of a nationwide epidemiological survey of tuberculosis. A total of 1105 subjects were screened out of whom 630 gave a history of BCG vaccination in the past and 363 were BCG-negative. Among BCG-negative children aged 5-14 years, only 5% had a positive Mantoux, a rate lower than most Third World countries but higher than developed countries were under 2% of children are tuberculin reactors. This calls for continuation of free treatment of active cases and increased efforts towards screening of contacts. The results also vindicate the current policy of giving BCG vaccine at birth and probably indicates the need to revaccinate at school leaving age, in accordance with WHO recommendations. Tuberculin reactivity rose steeply with age (32% at age 15-24 and 72% at age 45-64 years) indicating the presence of a large pool of subjects at risk of breaking into active disease. Finally, 71% (201/283) of children aged 5-14 years who had received BCG vaccine at birth, reacted negatively to the Mantoux test. This supports the findings of previous studies that in the majority of subjects, BCG-induced tuberculin sensitivity fades a few years after vaccination.     

Effectiveness of tuberculosis vaccines

BCG revaccination in the Sverdlovsk Region is performed thrice: at the age of 5, 10 and 15 years. The percent of children covered by tuberculin diagnosis and BCG vaccination is growing. Complications of BCG vaccination remain at the same level. Tuberculosis morbidity in children rises due to minor forms of tuberculosis. However, it is 2 times less than mean tuberculosis incidence in Russia. Primary infection is registered 4.5 times less frequently.     

Results of two-step tuberculin skin test against medical and nursing school students and treatment according to the results of the test]

To assess the risk of tuberculosis infection in medical and nursing school students, tuberculin skin tests were carried out in the two-step manner. The second tuberculin skin test was repeated two weeks later excluding those who were strongly positive in the first test. BCG vaccination was done with the consent of students who showed negative reaction twice. Medical interview and revaluation of prior routine chest radiogram were made on students who were strongly positive. Prophylactic INH medication was considered to those who are at high risk of tuberculosis. Eight hundred thirty eight students underwent the two-step tuberculin skin test, and among them, 771 students showed the positive reaction on the first test (92.0%) which included 58 weakly positive (6.9%), 347 intermediately positive (41.4%) and 366 strongly positive (43.7%) and 2 not-measurable (0.2%), and 65 students were negative (7.8%). The average size of the erythema was 30.9 +/- 18.8 mm on the first test and 37.9 +/- 20.6 mm on the second test. Twenty one students were negative on the second tuberculin skin test, and among them, 15 received BCG vaccination. Out of eight students who were vaccinated with BCG in 1999 and were followed up in the next year, 6 (75.0%) converted to positive. Strongly positive reaction was seen in 28 students (3.3%) and one of them underwent prophylactic medication of INH according to her family history of exposure to tuberculosis.     

The protective effect of BCG vaccination as indicated by autopsy studies

In a detailed study of the pathology of tuberculous infection made in Finland in 1961, tuberculous foci were found at autopsy in 61 of 67 non-vaccinated subjects and in 35 of 83 BCG-vaccinated subjects, all of whom had died between the ages of 1 and 45 years (with 2 exceptions from causes other than tuberculosis). In the present note on the same material, national information on tuberculin sensitivity and tuberculosis mortality has been used to calculate the risk of tuberculous infection in Finland at different times and ages during the lifetime of these subjects. From these risks of infection in Finland it was estimated that 63 or 64 of the non-vaccinated subjects had been infected during their lifetime and that between 25 and 31 of the BCG-vaccinated subjects were expected to have been naturally infected (had they not been vaccinated) between the time of vaccination and death. It is concluded that virtually all tuberculous infections in unvaccinated subjects lead to pulmonary foci, which are demonstrable at autopsy. Further, the same appears to be so in vaccinated subjects; there is no evidence to support the suggestion that in man BCG vaccine can prevent the establishment of infection in an exposed subject. The effects of BCG (as demonstrated in the earlier paper) appear to be confined to limiting the multiplication and dissemination of the bacilli and the development of lesions following infection.     

BCG scars in northern Malawi: sensitivity and repeatability of scar reading, and factors affecting scar size.

SETTING: Karonga district, northern Malawi. OBJECTIVE: To assess the sensitivity and repeatability of BCG scar reading, and factors affecting scar size. DESIGN: Follow-up of individuals aged > 3 months who were recruited into a BCG vaccine trial (1986-1989), and of infants vaccinated in health centres (1989-1991), who were examined for presence and size of BCG scars in subsequent years. All examinations were carried out blind of information on true vaccination status or the results of previous examinations. RESULTS: For trial individuals who were considered scar negative at recruitment and received BCG, the sensitivity of scar reading was > or = 93%, repeatability was > or = 94% for those < 60 years old at vaccination, and only around 1% were assessed as having > 1 BCG scar post-vaccination. For infants vaccinated when < 1 month old in health centres, the proportion who still had recognisable scars 4 years later was < 80%. Scars were larger in individuals with a prior BCG vaccination, and for those aged 15-59 at vaccination the scars were approximately 1 mm larger for males than for females. CONCLUSIONS: A BCG scar is a highly sensitive and repeatable indicator of vaccination status when the vaccine is properly handled, delivered appropriately, and given at over 3 months of age, but not for vaccinations given within 1 month of birth. Given that most vaccinations in the world are given soon after birth, this low sensitivity will lead to both vaccine coverage and vaccine efficacy being underestimated in studies in which vaccination status is inferred from the presence/absence of a distinctive BCG scar. Age-sex patterns identified for scar size show important similarities to those found with skin test responses to tuberculin.     

Vaccine protocols to optimise the protective efficacy of BCG.

SETTING: A deer model has been developed to study protection produced with BCG vaccination, against infection and the development of pathology, following experimental intratonsilar infection with virulent Mycobacterium bovis. OBJECTIVE: To determine how the dose of vaccine, the route of vaccination, the viability of the vaccine and exposure to glucocorticoids at the time of vaccination, may affect the protective efficacy of BCG vaccines. DESIGN: Deer were vaccinated with BCG and later challenged with virulent M. bovis via the tonsilar route. Protection against infection and development of disease was evaluated at necropsy six months after challenge with M. bovis, by histological examination and microbial culture. RESULTS: Significant protection against infection and disease were obtained following boosting with two low doses (5 x 10(4) cfu) or moderate doses (5 x 10(7) cfu) of live (freshly cultured and lyophilized) BCG. Inferior levels of protection were obtained with high dose (5 x 10(8) cfu) of live BCG. Similar levels of protection were found with vaccines given subcutaneously or via the tonsilar route. Killed vaccine in a mineral-oil adjuvant did not evoke protective immunity and treatment with dexamethasone prior to vaccination with live BCG ablated its efficacy. Protection against infection did not correlate with skin test delayed type hypersensitivity (DTH) or lymphocyte transformation to tuberculin. CONCLUSIONS: Two doses of live BCG gave significant protection against experimental infection and disease caused by virulent M. bovis. Single dose vaccine protected against disease but not infection. Vaccines administered at a dosage which did not evoke DTH, provided protection against tuberculosis infection and disease.     

Persistence and boosting of bacille Calmette-Guérin-induced delayed-type hypersensitivity.

BACKGROUND: Bacille Calmette-Guérin (BCG) vaccination may induce persistent and booster purified protein derivative (PPD) responses that complicate tuberculosis screening efforts. OBJECTIVES: To investigate the effects of BCG vaccination on serial PPD tests and to study correlations between persistent delayed-type hypersensitivity and other potential surrogate markers of protective immunity. DESIGN: Cohort study. SETTING: Midwestern urban university. PARTICIPANTS: 69 healthy adults. INTERVENTIONS: BCG vaccination, blood samples drawn for immunologic studies, and PPD tests done sequentially over 1 to 3 years. MEASUREMENTS: Serial PPD induration, lymphoproliferation, and interferon-gamma responses. RESULTS: 10% of participants (95% CI, 4% to 20%) had persistent PPD responses of 15 mm or greater, and 3% (CI, 0% to 10%) demonstrated PPD boosting of 15 mm or greater 1 to 3 years after BCG vaccination. Intradermal BCG vaccination induced a larger number of persistent responses that were 10 mm or greater than did percutaneous BCG vaccination (12 of 46 participants compared with 1 of 23 participants; P = 0.05). Persistent and boosted delayed-type hypersensitivity correlated with mycobacterial-specific lymphoproliferation and interferon-gamma responses. CONCLUSIONS: Previous BCG vaccination reduces the predictive value of serial PPD testing. The lowest PPD predictive values will occur in persons without known tuberculosis exposure who were vaccinated recently or many times with intradermal BCG. In addition, BCG-related persistence and boosting of delayed-type hypersensitivity responses correlate with other potential surrogate markers of protective mycobacterial immunity.