When comparing 1971-1972 with 1999-2000 NHANES data, we found a significant decline in LTBI prevalence among people born before 1926 but not for younger birth cohorts. Differences in LTBI prevalence in a birth cohort over time are a balance between new infections and waning of immunologic response to previous infections [3
]. Our data suggest that for older birth cohorts, the balance is in favor of waning response to previous infections. For younger birth cohorts, the acquisition of new infections may tip the balance in the other direction.
Loss of immunologic reactivity to Mycobacterium tuberculosis
in humans can be demonstrated by "two-step testing" with purified protein derivative (PPD), such as during repeated screening of healthcare workers. People who test negative in response to the first PPD test and subsequently test positive after a second test within a short period of time (~ 2 weeks) are thought to represent immunologic boosting of a previous infection [3
]. Some studies have reported that PPD boosting is associated with age. Among hospital workers in Saudi Arabia, immunologic boosting was more common among workers over the age of 45 than younger workers [5
]. Similarly, boosting was more than three times as common in employees 45 years and older than younger employees in a study of 10 hospitals throughout the United States [6
]. In contrast, a study in young (mean 21.4 years) healthcare workers in Montreal did not find an association between boosting and age [7
]. Perhaps waning reactivity to PPD is not observable before a certain age, such as 45 years.
A potential limitation of our analysis is that LTBI prevalence estimates were based on reaction to PPD S-1, which could include false-positive results based on reactivity to nontuberculous mycobacteria (NTM) or bacillus Calmette-Guérin (BCG) vaccination [8
], An alternate definition of LTBI incorporating results for PPD-Battey in addition to PPD S-1 to assess NTM cross-reactivity yielded no significant differences in prevalence estimates compared with LTBI based on PPD S-1 alone [1
]. Furthermore, the 1999-2000 NHANES reported a higher prevalence of NTM sensitization compared with the 1971-1972 NHANES, and this difference was significant among foreign-born persons [10
]. Increases over time in reactivity to NTM would increase LTBI prevalence estimates, rather than contribute to decreases in LTBI that we report. In addition, the waning effect of BCG vaccination is not likely to bias our findings. Prevalence estimates considering foreign-born individuals with a BCG scar as not having LTBI did not differ from estimates ignoring BCG scars [1
]; moreover, the NHANES foreign-born population was larger in 1999-2000 than 1971-1972, thus, potential misclassification due to BCG would result in higher, rather than lower, LTBI estimates in 1999-2000. Nonetheless, future research on LTBI will benefit from newer diagnostic technologies with higher specificity for M. tuberculosis
, such as interferon gamma release assays[11
]. We did not analyze data separately for persons who had ever been prescribed treatment for TB or LTBI since this group represented only 1.3% of the total population in 1999-2000 NHANES [1
The reduced LTBI prevalence among earlier birth cohorts that we observed could be influenced by selective mortality, to the degree to which people with LTBI progress to TB disease and die from TB or comorbid conditions. Since LTBI is more prevalent among vulnerable populations [1
], people with high rates of LTBI in earlier birth cohorts may experience higher mortality, resulting in lower LTBI rates among survivors. We cannot directly evaluate the influence of self-cure of TB, waning immunity, or selective mortality, since we compared birth cohorts across NHANES sample years, rather than longitudinal follow-up of the same individuals over time. Another limitation was small sample size in some cells, which restricted our ability to stratify analyses. Finally, data were not available for a detailed analysis of people born before 1912 or after 1946. However, comparison of LTBI prevalence -- a relatively rare outcome -- is strengthened by our use of large, nationally representative samples with consistent TST protocols. NHANES household sampling mitigates potential bias, in that the most vulnerable populations for LTBI (homeless or incarcerated people, and residents of long-term care facilities) are excluded. Importantly, our findings did not appear to be driven by greater inclusion of foreign-born people in 1999-2000 NHANES, as results were similar when restricted to the U.S.-born.