Transmission of Multidrug-Resistant Tuberculosis
Limited by Man or Nature?

Charles L. Daley, M.D.

University of California, San Francisco, California

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A global survey conducted by the World Health Organization and the International Union Against Tuberculosis and Lung Disease (1) found resistance to the standard antituberculosis drugs in all areas examined. This survey, as well as outbreaks of drug-resistant tuberculosis (2), has raised concerns about the potential of drug-resistant strains of Mycobacterium tuberculosis to spread widely and to undermine global tuberculosis control efforts. Of particular concern is the occurrence of multidrug-resistant tuberculosis (MDR-TB), defined as resistance to at least isoniazid and rifampin. Patients with MDR-TB respond poorly to conventional therapy, are costly to manage, and may remain infectious for prolonged periods of time. Thus, it is important for us to develop a thorough understanding of the potential epidemiological impact of resistant strains and to develop strategies for the effective management of MDR-TB.

In this issue of the AJRCCM (pp. 812-817), Nitta and colleagues (3) describe the "limited transmission" of MDR-TB in Los Angeles County, California, and review their approach to treating MDR-TB. The authors evaluated contacts to MDR-TB cases and used IS6110-based genotyping to identify secondary cases. Of the 102 cases of MDR-TB diagnosed during 1993 to 1998, only 8 (7.8%) cases were clustered. Six percent of the contacts to the MDR-TB cases were reported to have converted their tuberculin skin test (TST). Based on these findings, the authors concluded that there was "limited transmission" of MDR-TB and that one potential reason for this was the excellent tuberculosis control activities in Los Angeles. However, another possible reason for the "limited transmission" was not mentioned: perhaps drug-resistant strains of M. tuberculosis are either less transmissible and/or less pathogenic than drug-susceptible strains.

The pathogenesis of M. tuberculosis can be divided into three phases: transmission/acquisition of infection, containment/latency, and reactivation of latent infection. TST conversion rates among contacts provide a measure of the amount of transmission and infection that has occurred. Molecular epidemiologic assessments require the development of active tuberculosis and, thus, it is not possible to determine which of the different phases are affected. The effectiveness of the tuberculosis control program would modulate these complex host-pathogen interactions. Can the study by Nitta and colleagues (3), which used both TST conversion rates and genotyping data, answer the age-old question: is transmission limited by man or nature?

Nitta and colleagues report a 6% (58 out of 946 subjects) TST conversion rate in contacts to MDR-TB cases and note that this rate is lower than reported previously (4). Unfortunately, the authors did not compare the TST conversion rate of contacts to MDR-TB cases to that of contacts to drug-susceptible cases, making it difficult to interpret the results. Furthermore, the reference (4) to which the 6% conversion rate is compared, was reported in 1974, did not define TST conversion, and evaluated the contacts of only 40% of the cases identified. A better comparison is the recent publication in the AJRCCM by Marks and colleagues (5) who described the outcomes of contact investigations in several jurisdictions, including Los Angeles County. In that report, the conversion rate was 4% among all contacts and 8% among foreign-born contacts: not very different from the 6% conversion rate among contacts to MDR-TB cases in Los Angeles (3). Finally, because the majority of the MDR-TB cases and contacts came from high incidence countries, it is likely that many of the contacts had a positive TST already. These data are not provided, so it is difficult to determine the true TST conversion rate and thus, if transmission was truly "limited."

As noted earlier, genotyping studies are unable to determine which of the three phases of the pathogenesis of tuberculosis are affected. Nevertheless, the authors concluded that transmission of MDR strains was limited because the proportion of clustered cases is low (7.8%) compared with that reported in previous publications (6). There may be alternative explanations, however, for the low proportion of clustered cases among the MDR-TB cases in Los Angeles. First, in this relatively small study with strain typing available in only 76% of the MDR-TB cases (and none of the drug-susceptible cases), the observed cluster rate is likely an underestimate of the actual cluster rate (7). Second, the low clustering rate and small cluster size in the MDR-TB cases in Los Angeles may be partially related to the fact that 79% of the cases were foreign-born. In a study from San Francisco, only 12% of foreign-born cases were clustered compared with 59% of U.S.-born cases (8). And finally, there were four additional clustered cases in which the epidemiology strongly suggested transmission (e.g., siblings with similar drug susceptibility results) but had slight changes in the genotyping patterns, a finding which has been described previously (9). Therefore, I believe there was evidence of transmission in these additional cases increasing the overall clustered proportion to 12%, similar to that seen in foreign-born cases in San Francisco.

Nita and colleagues (3) suggest that "aggressive surveillance and case management were critical to limiting the spread of multidrug-resistant tuberculosis." There is no doubt that good tuberculosis control practices will limit transmission of tuberculosis, and that the approach to treating MDR-TB that is used in Los Angeles is a model from which we can all learn. However, I suspect that the same level of intensive tuberculosis control measures was applied to interrupt transmission, regardless of drug susceptibility test results, and that most transmission had occurred by the time aggressive contact investigations were initiated.

So, does M. tuberculosis play a role in the cycle of transmission? Molecular epidemiology studies have reported that drug-resistant isolates are less likely to be associated with clustering compared with drug-susceptible isolates (10). In addition, studies have shown that isoniazid-resistant strains cause significantly less disease in guinea pigs than drug-susceptible strains, and that mutations or deletions within the katG gene result in a decrease in the pathogenicity of isoniazid-resistant strains of M. tuberculosis (11). Thus, by being less fit, it is possible that drug-resistant strains of M. tuberculosis had something to do with the limited spread of disease in Los Angeles.

Based on the data presented, it is difficult to determine if there was "limited transmission" of MDR strains of M. tuberculosis in Los Angeles, at least compared with other control programs or drug-susceptible organisms. Eventually, studies of the transmission of M. tuberculosis will need to account for the role of tuberculosis control activities, the host, and the pathogen. Until then, we are left with the question, was transmission of MDR strains of M. tuberculosis in Los Angeles limited by man or nature? I think it was a little of each.

	References

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