July 2, 2008

Catch Them While You Can!

By DeRiemer, Kathryn De Jong, Bouke C

The estimated 9.2 million new cases of tuberculosis (TB) and 1.7 million annual deaths from TB during 2006 are a bleak reminder that new, creative strategies are needed to prevent and controlTB worldwide (1). For the past 15 years, molecular epidemiologic techniques have been used to identify clusters of TB cases whose isolates have identicalDNAfingerprints or genotypes, indicating recent transmission of Mycobacterium tuberculosis (2). In this issue of the Journal (pp. 96-104), Kik and colleagues determined that four specific characteristics of the first two TB cases in a genotypic cluster can predict whether the cluster will expand to five or more TB cases within 2 years (3). These results indicate that if we catch them early on, wecould prevent genotypic clusters of TB from becoming large. The study by Kik and colleagues has several outstanding and novel components. The authors worked with data from the world's largest population-based study of the molecular epidemiology of TB, an invaluable international resource. Incollaboration with the National TB Registry of the Netherlands, they accessed over 18,000 diagnosed TB cases nationwide from 1993 through 2004 and meticulously genotyped isolates of M. tuberculosis from over 9,000 culture-confirmed TB cases. Their clever analysis extends traditional multivariate logistic regression techniques to estimate the predicted probability that a large cluster will occur in the population.

The retrospective study's main finding-that large clusters can be predicted based on the characteristics of the first two cases-adds new knowledge to our understanding of the transmission of M. tuberculosis and provides a practical tool for public health programs. The authors determined that intensified contact tracing of the first two TB cases in a genotypic cluster would be justified if such TB cases had characteristics that were independently associated with large genotypic clusters (>/=5 TB cases): age under 35 years old, residence in an urban area, TB diagnosis within 3 months of each other, and of sub-Saharan African origin for at least one of the two TB cases. If the first two TB cases had none of these characteristics, the probability that the cluster would increase to five or more cases was 1%, versus 56% if the first two cases had all four characteristics. The authors further calculated that focused, intensified case finding would need to be performed in the Netherlands approximately 22 times per year to "intercept" clusters at risk of growing to five or more TB cases. The prospect of performing contact tracing for all infectious TB cases is daunting, particularly in high-burden countries. Therefore, the proposed strategy to focus contact tracing around the first two TBcases of only those genotypic clusters that are likely to becomelarge could be a feasible alternative.We anticipate that the authors will prospectively implement a case-finding strategy in the Netherlands based on their findings, and will track the costs, benefits, and impact of such a programover at least a 2-year period.

The relatively low incidence of TB and the low prevalence of HIV infection among TB cases in the Netherlands limit the inferences that the study's results will have in populations with a high burden of TB and HIV coinfection, for whom the need to optimize TB control efforts is great. Persons with TB/HIV coinfection are more likely to rapidly progress to active disease and genotypic clusters with at least one HIV-infected person can be larger, last longer, and have a shorter time between successive cases relative to clusters with only HIV-uninfected persons (4). Similarly, the authors include an analysis of bacterial factors contributing to differences in cluster size, and report that neither the strain lineage of M. tuberculosis nor drug resistance to the first-line anti-TB medications was independently associated with the development of large genotypic clusters of TB cases within a 2-year period. However, there are recent reports of large genotypic clusters of TB/HIVcoinfected cases with multidrug-resistant (MDR) and extensively drug-resistant (XDR) TB (5, 6). Extensive transmission of M. tuberculosis may occur before the initial cases are even diagnosed. In settings with a high prevalence of TB/HIV coinfection and/or a high prevalence of MDR TB and XDR TB, the risk factors for cluster growth may be different and more aggressive case-finding strategies could be necessary. The risk factors that are independently associated with enlarging clusters of TB cases may vary across different populations, but can still inform local case finding.

Can we hope for improvements in TB prevention and control in the near future? Until more sensitive diagnostic tests, shorter treatment regimens, and effective vaccines are available, we continue to rely on improvements in public health interventions, such as improved case finding and treatment success (7). If existing rapid genotyping methods, such those based on mycobacterial interspersed repetitive unit (MIRU) loci and the variable number of tandem repeat (VNTR) (8) and their modifications (9, 10), were combined with molecular tests to detect drug resistance-conferring mutations (11), the appropriate treatment regimens for active and latent TB infection could be assigned to contacts identified through active case finding. Rapid molecular diagnostic tests are increasingly available and could soon become a common tool in clinical diagnostic laboratories to detect mycobacteria (12). In the future, we may have the capacity to rapidly identify genomic DNA of M. tuberculosis and other mycobacteria in clinical specimens from TB cases without the need for culture (13), and simultaneously identify drug resistance-conferring mutations. If we could also rapidly identify new clusters of TB cases at the population level, we could intervene in time to prevent them from enlarging. We need to be clever and quick to limit further transmission and new cases of M. tuberculosis worldwide.

Conflict of Interest Statement: Neither author has a financial relationship with a commercial entity that has an interest in the subject of this manuscript.


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DOI: 10.1164/rccm.200804-589ED


University of California, Davis

Davis, California


New York University

New York, New York


MRC Laboratories

Banjul, The Gambia

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