According to these findings, ≈1 in 4 TB cases reported in the United States may be attributed to recent TB transmission; this increases to 1 in 3 among US-born persons (). Our approach to identifying the proportion of reported TB attributable to recent transmission is based on the concept that epidemiologically related organisms share indistinguishable genotypes, whereas unrelated organisms differ at some genetic loci (8
). TB cases that occur in spatial clusters and share indistinguishable genotypes are thought to be caused by recently transmitted TB infection; those with nonclustered genotypes are thought to result from progression from an infection acquired >3 years in the past. In the absence of detailed data about interpersonal contact between persons, relying on genotype and on place and time data routinely collected during surveillance activities becomes imperative to assessing recent transmission at a national level. This goal was achieved by using the established infrastructure of NTSS and TB genotyping, universally accessible to TB programs through NTGS, to capture 72% of all cases with culture-positive results over a 5-year period.
Spatial scanning provides a new insight into TB transmission that is independent of jurisdictional or geopolitical boundaries. This nationally representative study incorporated spatial concentration as a core element for defining recent TB transmission. Previous studies were limited to clustering definitions confined to a single jurisdiction (9–11,14,15
), state, or province (28,29
), or incomplete sampling of an entire nation (13
). The proportion of cases representing recent TB transmission varied considerably by cluster definitions based on geopolitical borders. If a national clustering definition was used, up to 80% of culture-positive cases would be attributed to recent TB transmission. If a state-based definition or county-based definition was used, up to 57% and 39% of culture-positive cases, respectively, would be attributed to recent TB transmission. Although which definition most accurately represents recent TB transmission is unclear, a clustering definition based on geospatial concentration appears to be the most conservative and is not subject to the potential misclassification of political boundaries. The limitation of using these boundaries can be best exemplified by known inter-jurisdictional TB outbreaks that crossed geopolitical borders (31
). Because the proportion of recent TB transmission may be a reflection of the success of control measures, accurately assessing this quantity is of considerable public health importance.
Estimating recent TB transmission also depends on the duration of the study period (16
). Other studies have shown increasing clustering proportions as the duration of the study increases, with a plateau effect after 3 years (12,13,17,32,33
). The annual proportion of isolates with a new strain identified in the United States during this study period did plateau (data not shown), suggesting a similar phenomenon and potential influencing factor in the long-term estimation of TB genotype clustering nationwide. Using consecutive, overlapping scanning windows that incorporate 3-year intervals maximizes the probability that spatial and temporal clustering represent localized, recent TB transmission within this large and comprehensive dataset. As NTGS continues to mature and grow over time, adjusting for temporal clustering will become essential when estimating recent TB transmission.
Consistent with other published reports from countries with a low incidence of TB, the characteristics of local birth, male sex, minority race, substance abuse, and homelessness were associated with recent TB transmission (17,18,33
). These findings highlight the fact that TB may be harder to eliminate among populations characterized by these factors (34
). The large proportion of cases attributable to recent TB transmission among minorities, persons who abuse substances, and those who are homeless suggests that limited access to routine health screenings, resulting in delayed diagnoses, may extend infectious periods and rates of TB transmission. Indeed, TB patients who use illicit substances and abuse alcohol have been found to be more contagious (24
In low-incidence, high-resource countries, efforts to control recent TB transmission are based largely on contact investigation, yet for many reasons, contact investigations may not be sufficiently intensive or comprehensive, even in successful TB control programs (35
). Every case of TB began when a person came into contact with a person with contagious TB. Therefore, it follows that clusters of case-patients representing recent TB transmission could be averted through improved contact investigation efforts. Contact investigations are multistep processes in which exposed contacts are systematically evaluated on the basis of the amount of time spent with an infectious person, the environmental conditions of exposure venue, and the contact's intrinsic predisposition for infection or disease (36
). Numerous studies have demonstrated that eliciting names of contacts is neither optimally effective nor sufficient to interrupt TB transmission among high-risk groups, such as the homeless and persons who abuse substances (1,24,37,38
). The potential for uninterrupted TB transmission is further exacerbated by the poor yield of name-based contact investigations among these populations. Locations are as important as named contacts when investigating recent transmission. A recent study found that 81% of case-patients involved in a multiyear TB outbreak lived in close geographic proximity (38
). Spatial scanning methods may assist with identification of specific clusters representing ongoing transmission that could benefit from targeted location-based interventions. Using spatial scanning methods to determine locations with high concentrations of both spatial and genotype clustering may be an effective way to prioritize resources to intervene in populations with high rates of TB transmission.
This study does have limitations. First, isolate submission for TB genotyping is not universal; thus, the database, although large, did not contain all reported case-patients with culture-positive TB during the study period. Clinical, demographic, and epidemiologic characteristics of patients without TB genotyping data did not differ statistically from those with TB genotyping data (data not shown). Second, spatial and genotype clustering serves only as a proxy for recent TB transmission in the absence of detailed data on interpersonal connections between case-patients. Because of dynamic migration patterns within the United States, these methods may fail to ascertain cases that are due to recent transmission when a putative source case-patient moves or if exposure occurred outside the range of spatial scanning. Increased global migration has influenced the epidemiology of TB in the United States as well. Recent immigrants who became infected with a particular genotype elsewhere may resettle in the same neighborhood and, when TB develops after resettlement, it may falsely be considered recent TB transmission. Third, although spoligotyping and 12-locus MIRU-VNTR have good discriminatory power, these methods may not provide the resolution necessary to differentiate evolutionarily close strains (39,40
). The introduction of an expanded panel of 24 MIRU-VNTR loci in 2009 to NTGS may reduce this misclassification in the future (40
). It is also critical to note that TB transmission dynamics are multifactorial. TB genotype clustering may overestimate transmission. Consideration of patient characteristics, transmission venues, and temporality may better clarify recent transmission.
The integration of NTGS into routine public health practice and surveillance has led to the establishment of molecular surveillance of M. tuberculosis in the United States (20). With improved access to and rapid dissemination of genotyping information, it may be possible to more effectively identify some cases of TB transmission. Yet, TB genotyping, and likely future molecular advancements do not alter real-time public health action. Rather recent transmission can only be prevented by implementing thorough contact investigation and ensuring that subsequent preventive treatment is completed among those identified at highest risk of undergoing a progression from infection to TB disease. If such practices had been successfully followed, as many as one third of all reported TB cases in US-born patients may have been prevented, especially among high-risk populations, such as persons with substance abuse disorders, those experiencing homelessness, or both. Greater attention and resources are needed to develop, implement, and evaluate interventions to control and prevent transmission among these populations. As the United States continues toward TB elimination, understanding transmission dynamics among high-risk populations and establishing new strategies for rapidly detecting and effectively responding to these transmission events will enhance the progress toward achieving this target.