© 2005 American Thoracic Society doi: 10.1164/rccm.2502005
Are Some People Not Safer after Successful Treatment of Tuberculosis?Tuberculosis and Chest Unit, Grantham Hospital, Hong Kong, China Contrary to the intuitive perception that previous tuberculosis often results in partial immunity (1), the study by Verver and coworkers (2) in this issue (pp. 1430–1435) demonstrates that the rate of reinfection tuberculosis after successful treatment is four times higher than the rate of new tuberculosis in an area with high prevalence of the disease. This novel finding is conceptually important because of its potential implications in tuberculosis control and vaccine development. Two possibilities exist to explain these results, neither of which is mutually exclusive: (1) the selection of individuals with predisposition to tuberculosis infection/disease or (2) that tuberculosis itself increases the vulnerability to reinfection/disease. Disparate rates of tuberculosis infection have previously been demonstrated within different segments of population (3, 4). Increased susceptibility to development of disease is also well reported among various patient groups (5, 6). In a recent study in Hong Kong, men aged 65 years or older who smoke were shown to have an incidence of tuberculosis seven times greater than that of the general population (7). Increased rates of tuberculosis in a population subset may result in an apparent increase of recurrent tuberculosis in patients after successful treatment. To take a simple example, if 20% of the community has an incidence of disease three times that of the general population, then this high-risk segment will be overrepresented in the tuberculosis patient population (3 x 20% = 60%), and the incidence of disease among the entire patient group will appear to be increased by twofold. After an episode of tuberculosis, "negative" immunity with increased vulnerability to development of disease might be rather unlikely, but increased risk of exposure may still arise within the health care settings. Indeed, the lower incidence of reinfection disease noted in Verver and colleagues' study among the defaulters, who interrupted treatment for a minimum of 2 months or were never treated, is consistent with this possibility. A few caveats must also be borne in mind when interpreting the findings of this epidemiologic study. First, the percentage of available DNA fingerprints is relatively low (70%) as compared with another population-based study of a similar nature (8), as is the substantial percentage of solitary positive cultures in comparison to other studies (5). Although it would not be fair to speculate on the magnitude of false-positive cultures, such a possibility could exist. On the other hand, Verver and colleagues state that their laboratory error rate was only 3.4%, a figure that indeed closely corroborates the findings of another study that has addressed DNA fingerprint changes in tuberculosis (8). They also stress that, after excluding those episodes with single-positive cultures from the analysis, there is still a similar proportion of recurrences attributed to reinfection: 71% after successful treatment and 13% after default. However, after excluding cases with single-positive cultures, disease rates related to confirmed or likely reinfection were much lower, being only approximately twice the age-adjusted incidence rate of new tuberculosis for the entire population of the community. Second, although some characteristics of the study cases with available DNA fingerprints have been provided, other possible confounders, such as HIV status or socioeconomic background, were not investigated among the study patients and compared with the overall population (3–5, 9). HIV infection is a risk factor for both endogenous relapse of tuberculosis and rapid progression to disease after exogenous tuberculosis infection. The relative contribution of each process will determine the relationship with clustering. Some studies have found an increased risk for tuberculosis clustering among patients with HIV (10, 11), but others have found no association between HIV infection and such clustering (12–14). A recent investigation undertaken in northern Malawi in Africa has revealed that a higher proportion of recurrent tuberculosis caused by reinfection after treatment occurred among HIV-positive individuals than HIV-negative subjects: 58 versus 0% (8). Furthermore, a study conducted in African mineworkers has revealed HIV infection as a risk factor for recurrence of tuberculosis after cure (hazard ratio, 2.4) because of its strong association with disease caused by reinfection (hazard ratio, 18.7), but not relapse (hazard ratio, 0.58) (5). Thus, assessment of factors such as secondary chemoprophylaxis and/or antiretroviral treatment was suggested for these subjects.
Verver and coworkers have alluded to the scenario of dual infection with M. tuberculosis, of which one strain was cultivable during the first disease episode, and the other strain during the recurrent episode. Distinguishing between "new" reinfection and dual infection initially followed by such reactivation of one strain may not be easy. Nevertheless, the likelihood of tuberculosis caused by multiple strains fortunately does not appear to be high ( The messages derived from the present study might merit exploration in tuberculosis program enhancement, especially regarding case finding and preventive therapy among at-risk population groups in areas of high disease prevalence. Most phase III trials on new antituberculosis drugs rely on recruitment from these areas, and use bacteriologic relapse as the primary endpoint to assess chemotherapy efficacy. If over two-thirds of such "relapses" are not true relapses, validation with molecular techniques may be necessary. FOOTNOTES Conflict of Interest Statement: W.W.Y. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript; C.C.L. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. REFERENCES
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20%), and findings from molecular epidemiologic studies still provide reasonably valid information (