In the absence of molecular epidemiologic data, secondary cases of MDR TB within a household are generally assumed to be the result of within-household transmission. In an area with increasing incidence of MDR TB (20
), we found that 90% of household contacts of MDR TB index cases with active disease and drug-susceptibility test results had MDR TB (29
). Our present study, in a subset of that cohort, used genotyping on the basis of spoligotyping and 24-loci MIRU-VNTR, which has been shown in other settings to have comparable discriminatory power to IS6110
). Our study shows that there was at least a 10% risk that a subsequent case of MDR TB occurring within the home of a known MDR TB patient was the result of transmission in the community rather than transmission in the household. This estimate represents a lower boundary of the contribution of community transmission to the appearance of secondary MDR cases within a home because matching strains within a household (which we would categorize as within-home transmission) may be caused by transmission from other sources in the community. Because circulating MDR strains were heterogeneous (), the magnitude of this bias may not be substantial.
Strain lineages of Mycobacterium tuberculosis detected in the study population, Lima, Peru, 1996–2004
We did not find any easily measured household factors associated with risk for repeated introductions compared with within-home transmission. We had hypothesized that a high household density (persons/bedroom) or low quality of household structure may be associated with a higher probability of within-home transmission, conditional upon observing multiple cases within a home, but this hypothesis was not supported by these data. This finding may reflect an absence of this association between household characteristics and risk for within-home transmission or, alternatively, it may reflect the relatively small number of repeated introduction events that we observed and our limited power to test such associations. Accordingly, although our observations provide convincing evidence that repeated introduction of MDR TB into households occurs in these settings, further studies are needed to determine whether household factors, number of persons within these households, or strains present within these households are associated with an increased risk for within-home transmission or repeated exposure in the community.
) or acquired susceptibility (34
) to infection and disease may play a role in the accumulation of multiple TB cases within households. Because household members are likely to share genetic or environmental risk factors, or both, persons living with TB case-patients may be particularly likely to be infected and acquire disease whether they are infected by their household contact or in the community.
Our findings provide evidence to support international guidelines for management of active TB among contacts of known MDR TB cases (17–19
) because they confirm that among strains from persons for which genotyping test results are available, <
90% of household contacts with MDR TB were infected with the same strain as the index patient. Our findings also highlight limitations associated with such policies. Because subsequent cases of MDR TB in a household may be caused by community transmission, policies that specify that apparent secondary case-patients receive therapy on the basis of the drug-susceptibility profile of an isolate from the initial MDR TB patient may result either in effective drugs being needlessly withheld or in administration of drugs to which the strain is already resistant. This policy may result in acquisition of additional resistance to second-line drugs and prolonged opportunity for transmission of highly drug-resistant strains within homes and in the community (35,36
These findings support the use of rapid drug-resistance tests to determine drug susceptibility profiles in known contacts of MDR TB patients. Molecular tests for resistance, such as line probe assays and cartridge-based PCRs (i.e., GeneXpert; Cepheid, Sunnyvale, CA, USA), are promising and have been endorsed by the World Health Organization for determining resistance to first-line drugs (37
). However, although new diagnostic tests in development also detect resistance to second-line drugs (38,39
), these tests have not yet been optimized for use in guiding clinical care. New rapid phenotypic tests for resistance, such as the microscopic-observation drug-susceptibility assay, have also not yet been adequately tested under field conditions for their capacity to be used in selection of tailored regimens for MDR TB (40
). Known contacts of MDR TB patients should be a high-priority, high-yield study population for assessing the immediate utility of these new tools.
A limitation of our study is that we cannot definitively distinguish the 2 mechanisms by which distinct MDR isolates may appear within households. First, household members may have been infected by different drug-susceptible strains in the community and acquired drug resistance through deficient drug treatment. Second, household members may have been directly infected by different MDR strains in the community. Distinguishing between these 2 possibilities is essential because each would cause a distinct public health response. The first mechanism suggests that detailed investigation of individual-level or household-level risk factors for acquisition of MDR TB was needed and would indicate a need for greater treatment support and supervision for patients with drug-susceptible disease. The second mechanism indicates a need to improve infection control in the community or to facilitate diagnosis and effective treatment for persons with MDR TB to reduce the duration of infectiousness. In most circumstances, we expect acquisition and transmission to contribute to the appearance of multiple cases of MDR TB within homes, and efforts to reduce the incidence of drug-resistant disease will need to address these factors.
Although we have insufficient data for previous TB episodes and treatment for persons in our study to exclude possible independent acquisition of MDR TB among household members because of inadequate treatment, our finding that >4 persons showed evidence of reinfection by a second (i.e., different) MDR TB strain provides evidence that there is a high risk for MDR TB exposure in this community. HIV status was known for only ≈50% of the persons in the study. Among those tested, only 3 (3%) of 102 were HIV infected and none of the 3 HIV-infected persons were among persons in households in which multiple introductions of MDR TB were detected. If co-infection with HIV was common, it would be expected to increase the probability of rapid progression to disease and lead to higher risks of multiple cases of unlinked disease within households. Because HIV co-infection was so rare, it is unlikely that this explains the study results.
Our results extend findings from previous studies showing that a substantial fraction of cohabiting persons have independently acquired TB in the community (13–16
). In contrast to earlier studies that compared relative contributions of within-home and community transmission, all persons in our study had MDR TB. We found that although 90% of households had evidence of intrahousehold transmission, 10% had >
2 independent introductions of MDR M. tuberculosis
strains from the community. This finding suggests that the risk for community or extrahousehold transmission of MDR TB in Lima is high. Furthermore, it indicates that known MDR TB contacts initiating empirical treatment for MDR TB treatment require access to drug susceptibility testing to ensure that they receive the drugs to which their isolate is susceptible. National TB programs should be wary of applying empirical regimens on the basis of population-level drug susceptibility data without better understanding of the relative role of intrahousehold and community transmission of MDR TB.