© 2006 American Thoracic Society doi: 10.1164/rccm.200607-923ED
Here Today—Gone Tomorrow: The Case for Transient Acute Tuberculosis InfectionHarvard Medical School, Brigham and Women's Hospital, Boston, Massachusetts
Pharmaceutical Products Development (PPD), Washington, DC
Along with death and taxes, another widely known certainty of life (within medical circles at least) is that once infected with Mycobacterium tuberculosis, human hosts carry the organism in a latent state to the grave, with a relatively small and diminishing risk of reactivation along the way. So secure are we in this perceived wisdom that no further skin testing is done for tuberculin skin test (TST)-positive persons. Of course, skeptics have repeated skin tests, and for decades reports of TST reversions have appeared in the literature. Given the vagaries of the TST and our still incomplete understanding of the human immune response to this ancient pathogen, these reports have been considered no more than the exceptions that prove the rule. In this issue of the Journal, however, Ewer and coworkers (pp. 831–839) provide new observations among school contacts of an active case that prompt treatment of latent infection may lead to decreased antigen-specific IFN- The setting in which TST reversion can most convincingly be demonstrated is following treatment for latent TB infection. In a classic study of tuberculosis transmission on the destroyer U.S.S. Byrd, for example, the majority of 179 skin test converters subsequently reverted to negative after treatment with isoniazid (2). Other studies have documented skin test and IGRA reversions in up to half of treated health care workers, particularly in those individuals with small initial skin test reactions (3). IGRA reversion may also occur after treatment of active tuberculosis (4). Reversion in other contexts has been described less consistently. Indeed, some studies found TST and T cell blastogenic responses to be strongly maintained in healthy persons for years or even decades (5, 6). Nonetheless, among otherwise healthy, nonanergic elderly persons, Dorken and colleagues reported TST reversion occurring without treatment at an annual rate of 3% (7). In all of these settings, TST or IGRA reversion may reflect successful eradication of infection (as usually occurs after BCG vaccination, for example) or simply a reduction of antigenic burden below a threshold needed to maintain delayed type hypersensitivity, but with residual risk of reactivation. In humans, the fate of such infections is difficult to ascertain. However, autopsies of guinea pigs which had been exposed to exhaust air from a tuberculosis ward were reported to show little or no microbiological or pathologic evidence of active tuberculosis if the animals had small, non-necrotic TST reactions compared with those animals that progressed to large, necrotic reactions (8). Similar studies, ongoing in South Africa, where guinea pigs are exposed to patients with drug-resistant TB, are confirming self-limited disease progression associated with documented TST reversion of small reactions (personal communication, Dr. Karin Weyer, July 6, 2006, Pretoria, South Africa). A recent report by Pai and coworkers (9) supports the observation reported in this issue by Ewer and colleagues. The authors also found IGRA reversions occurring more often in health care workers with weak initial IGRA responses and negative skin tests. These authors considered the possibility of false-positive IGRA especially if the tests are regarded as dichotomous, and actual values are not considered. Generally, however, IGRAs are thought to improve on the TST in terms of reproducibility and specificity (10). They may also focus attention on defenses mediated by T cells of the effector memory subset (TEM) (11). Both factors may contribute to the present observations. Some caveats are in order, however. Since both reports identified the subset of interest retrospectively based on their initial response, they may be susceptible to the statistical artifact of regression to the mean, as well as the other recognized shortcomings of subset analysis. In addition, prospective studies should reduce the small possibility that such artifacts are playing a role. Differences in either innate or acquired host responses may account for these observations. TB-naïve individuals differ in their capacity to restrict intracellular M. tuberculosis growth (12). The impact of such differences on subsequent TST responses or TB risk is not known. Further prospective studies of IGRA reversion that include assessment of the capacity to control intracellular M. tuberculosis growth would help determine whether such persons indeed have heightened host defenses against TB, and, if so, may help identify the underlying cellular mechanisms. Finally, the clinical, public health, and pathophysiologic implications of these observations for patients are unclear. Should all positive skin tests and IGRAs be routinely repeated? Do tests that revert to negative require preventive treatment? The children tested in the study by Ewer and colleagues, having never been TST-positive and only transiently ELISpot-positive, would appear to be at very low risk, but we do not know for sure. Will transient acute TB infection affect subsequent TST or IGRA results? Hohmuth and coworkers recently reported greater TST boosting among TB-exposed medical and nursing students from Lima, Peru, compared with TB-unexposed university students, even though both groups had been BCG-vaccinated (13). Could transient acute TB infection among the health care students have primed their immune system? Answers to these practical questions await further studies, as does a deeper understanding of the mechanisms involved. FOOTNOTES Conflict of Interest Statement: E.A.N. has attended one advisory committee meeting for Oxford Immunotec, Ltd in 2005 and was reimbursed for expenses plus a $2,000 honorarium. R.S.W. does not have a finanical relationship with a commercial entity that has an interest in the subject of the manuscript. REFERENCES
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release, and more interestingly, that some exposed children with negative tuberculin reactions, but weakly positive ELISpot IFN-
