In Hong Kong, bacillus Calmette-Guerin (BCG) vaccination has been given to all newborns with a coverage rate of about 99% since 1970.1 The Glaxo strain of the vaccine was applied at birth through either intradermal or percutaneous route. Despite a relatively low risk of tuberculosis (TB) until the age of 14 years, TB risk increases rapidly after 15 years of age to a secondary peak in young adulthood.1 Similar observations have been reported in other populations, irrespective of BCG vaccination.2–4 Tuberculin reaction size in primary school children has been reported to predict TB disease between the age of 10 and 15 in Hong Kong.5 However, TB risk is known to fall off rapidly with time after infection.6,7 A prospective cohort study was therefore conducted to assess whether tuberculin reaction size in primary school children would predict TB in later adolescence.
STUDY POPULATION AND METHODS
A team of experienced skin test inoculators visited a total of 40 consecutive primary schools from October 1999 to February 2000. After obtaining consent from parents, we tested 95% of students from primary grade 1 to 4 with 1 unit of tuberculin (PPD RT-23) on the left forearm using the intradermal technique. The maximum transverse diameter of the induration was measured with a ruler after 72 hours. School children with tuberculin reactions at or below 9 mm were offered revaccination. In the absence of recent contact history, treatment for latent TB infection was not offered irrespective of tuberculin reaction size.5 Because of the wide BCG vaccination coverage in Hong Kong, targeted screening with tuberculin skin test was restricted mainly to infant contacts of smear-positive TB cases in the period concerned.
All students 6 to 10 years of age with a valid identity card number were included in this study. Their names, gender, dates of birth and dates of tuberculin testing, and exact tuberculin reaction sizes at 72 hours were recorded together with the identity card number from the school revaccination records. All subjects were followed up until December 31, 2010 by cross-matching with the territory-wide TB registry, using the identity card numbers as the unique identifiers. The medical records of all identified TB cases were retrieved from relevant chest clinics or hospitals for verification of identity, and confirmation of the diagnosis. An active case of TB was defined as disease proven by isolation of Mycobacterium tuberculosis, or in the absence of bacteriological confirmation, physician-diagnosed disease with compatible clinical, radiologic, and/or histologic features, together with an appropriate response to treatment.
SPSS version 14 (SPSS Inc, Chicago, IL) was used for statistical analysis. In univariate analysis, χ2 test or Fisher exact test was used for categorical variables and analysis of variance was used for continuous variables as appropriate. These were followed by logistic risk modeling for cross-sectional analysis and Cox proportional hazards modeling for prospective cohort analysis, with adjustment for gender and baseline age. Potential multicollinearity was considered. The proportional hazard assumption of the Cox model was assessed by inspection of the log minus log curve. A 2-tailed P value of 0.05 was taken as statistically significant.
Approval for the study was obtained from the Ethics Committee of the Department of Health of Hong Kong SAR, China.
A total of 25,970 school children 6 to 10 years of age were tuberculin tested between October 1999 and February 2000. Among them, 19,745 used the Hong Kong Identity Card number as their student number in transition to the revised student registration policy. The exact magnitude of tuberculin response or date of birth was not known for 362 school children, leaving 19,383 for analysis. The mean age was 8.37 ± 1.40 years (mean ± SD).
Table 1 summarizes the tuberculin-positive rates at different cut-off points for school children of different gender and age groups. At the cut-off points of ≥5, ≥10, and ≥15 mm, more females were tuberculin-positive than males (P < 0.001, P < 0.001, and P = 0.029, respectively). A significant linear trend was found between the tuberculin-positive rates and age at all cut-off points, and such linear trend persisted when separate analysis was applied to both genders (Table 1). On multiple logistic regression analysis, female gender independently predicted tuberculin positivity at the cut-off points of 5 mm (odds ratio: 1.32, P < 0.001) and 10 mm (1.39, P < 0.001), but not 15 mm (1.19, P = 0.079), whereas age independently predicted tuberculin positivity at all cut-off points (odds ratios: 1.12, 1.14, 1.17 per year at the respective cut-offs, all P < 0.001).
By December 31, 2010, 44 active TB patients (32 pulmonary only, 4 extrapulmonary, 8 both) were identified after 214,753 person-years of follow-up. Twenty-two cases (50%) were confirmed by culture, including 11 cases (25%) with positive sputum smear. The diagnosis of the rest was verified by their clinicoradiologic picture and subsequent improvement on anti-TB treatment. There were 22 females and 22 males (P = 0.881). The median age at disease onset was 16.8 (range, 11.9–20.6) years. The median interval from tuberculin skin testing to the development of disease was 3024 (range, 568–4109) days. All of these 44 TB patients reported good past health, except for 2 suffering from asthma, 1 with history of nephritis, and another with history of pneumonia. All of them had received BCG vaccination at birth and/or showed a BCG scar. Only 9 reported a history of TB contact (household contact: 7, nonhousehold contact: 2), 7 of which occurred within 2 years. Table 2 summarizes the incidence of TB in the cohort. For school children with baseline tuberculin reaction size of 15 mm or above, the incidence of TB was 608.1 (314.1–1061.9)/100,000 person-years beyond the age of 15 compared with 37.5 (1.0–209.2) per 100,000 person-years under that age (relative risk: 16.2, 95% CI: 2.1–124.5, Fisher exact test, 2-tailed P < 0.001).
Table 3 summaries the adjusted hazard ratios for active TB and culture-confirmed TB by the baseline variables of gender, age, and tuberculin reaction sizes. Figure 1 shows the adjusted TB hazard curves for different categories of baseline tuberculin reaction size. The risk of active TB remained low for all categories of tuberculin reaction sizes within the initial 3 to 4 years, after which primary school children with baseline tuberculin reaction size of ≥15 mm showed a marked and statistical significant increase in TB risk. Similar adjusted hazard ratios were obtained after excluding the 9 cases of active TB with contact history (Table, Supplemental Digital Content 1, https://links.lww.com/INF/A983). Table 4 summarizes the estimated number of children needed to be treated to prevent 1 case of TB in 10 years, assuming 100% efficacy of preventive treatment.
In this study, tuberculin reaction size of ≥15 mm in children predicted a 20-fold increase in risk of active TB in the subsequent 11 years compared with those with a reaction size below 5 mm (Table 3). In these strongest tuberculin reactors, the risk of TB increased by approximately 15 times after the age of 15 years.
Two previous studies also showed that tuberculin reaction size of ≥15 mm was associated with increased TB risk at a younger age and/or within shorter period follow-up.5,8 The current study provided new evidence that strong tuberculin reactions in children 6 to 10 years of age predicted the subsequent development of TB beyond the age of 15 years after an initial quiescent period, contravening the usual observation of decreasing risk of disease with the passage of time after infection.6,7 Reactivation of latent TB infection therefore accounted for the majority of TB cases among Hong Kong adolescents, in keeping with the low proportion of cases attributable to recent transmission in molecular clustering analysis.9 Long-term follow-up data in Alaska7 and Houston10 also suggested long-lasting protective effect of isoniazid treatment in children. While higher tuberculin-positive rates were observed in girls (Table 1), female gender did not independently predict strong tuberculin reaction (≥15 mm) or subsequently development of disease. This could suggest gender-related differences in BCG cross-reactivity rather than infection or disease risk.
In this study, the 10-year cumulative risk of TB of nearly 3% among the strongest tuberculin reactors was comparable with those reported among close contacts or other risk groups.11–15 Although older children with a positive tuberculin skin test alone are not generally considered as a priority group for treatment of latent TB infection outside the contact settings in areas with extensive BCG vaccination coverage,16 the findings of this study (Table 4) would support the use of preventive treatment for older children with a strongly positive TST irrespective of contact history and BCG vaccination status.
During the BCG revaccination program, BCG vaccination status and scar were not checked.17 However, the neonatal BCG vaccination coverage has been around 99% since 1970 in Hong Kong.1 Such a high coverage was supported by the presence of either a positive BCG vaccination history or scar in all the TB cases detected in this study. Because of the wide BCG vaccination coverage and concern over possible cross-reactivity, 1 unit of PPD-RT23 was regularly used for skin testing in Hong Kong during the period of study. Use of 2 units of PPD-RT23 might lead to a small increase in the number of strong reactors with minor dilution of the risk differential, but is unlikely to affect the overall result. Children with reaction sizes 10 to 14 mm and ≥15 mm were not revaccinated. With the risk differential observed between these 2 groups (Tables 2, 3), BCG revaccination was unlikely to confound the findings of this study. Data on loss to follow-up were not available, but excess mortality or emigration is not expected for this age group for the period concerned. With the internal comparison between different tuberculin reactor groups, incomplete case ascertainment alone is unlikely to affect the overall validity of the observations.
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