Academic journal article Bulletin of the World Health Organization

Molecular Epidemiology of Tuberculosis: Achievements and Challenges to Current Knowledge

Academic journal article Bulletin of the World Health Organization

Molecular Epidemiology of Tuberculosis: Achievements and Challenges to Current Knowledge

Article excerpt

Voir page 480 le resume en francais. En la pagina 480 figura un resumen en espanol.


Styblo defined tuberculosis (TB) epidemiology as "the study of the interactions between the tubercle bacillus and man in his environment (in a community)" (1), and remarked that it was particularly important to study them under natural conditions without any interference in the form of direct or indirect control measures. The data that Styblo relied on to assess the burden of clinical TB included case notifications based on the examination of sputum by microscopy, bacteriological cultures, and chest radiographs. Rates of TB infection were estimated from surveys involving serial tuberculin skin tests. These tools allowed him to &scribe the downward trend in the incidence of TB in Europe during the 20th century, to measure the mortality associated with untreated disease, to estimate infectiousness and to measure the contribution of exogenous reinfection to TB morbidity.

Notwithstanding the work of Styblo, Gryzbowski, Comstock, Stead, and others, many important questions remain unresolved, largely because the natural history of the disease makes it so difficult to study. The armamentarium has often been inadequate for studying patterns of occurrence of tuberculosis, especially in those areas of the developing world where its toll is highest. Surveys based on the tuberculin skin test are often difficult to interpret because of cross-reactivity with BCG vaccine and environmental mycobacteria. Case notification data continue to underestimate the disease burden in areas where the prevalence of TB is high but resources for diagnosis and record-keeping are limited. Until relatively recently it has not been possible to trace pathways of TB transmission within populations.

Unresolved issues in TB epidemiology

By the early 1990s, when molecular fingerprinting first appeared, many questions in TB epidemiology remained unresolved. They included the relative contributions of reactivation and primary disease in areas of high and low prevalence, risk factors for recent infection and/or primary disease, and the occurrence and frequency of exogenous reinfection. More recent issues include the impact of human immunodeficiency virus (HIV) coinfection on transmission, the infectiousness of smear-negative tuberculosis, the relative transmissibility of different strains, and other phenotypic differences among strains of M. tuberculosis.

Efforts to strain-type M. tuberculosis failed until the 1990s, when polymorphic sites were identified in repetitive sequences in the genome (2, 3). The most widely used marker is the transposable element IS6110 (4), which varies in both copy number and location in the genome. This marker is generally considered to be variable enough to distinguish between unrelated strains but stable enough to remain consistent in related strains. Limitations of molecular fingerprinting include its inability to distinguish between unrelated isolates with a low copy numbers.

Soon after their development the fingerprinting techniques were used to document the transmission of M. tuberculosis between contacts. Daley et al. described 12 cases of TB that occurred in a housing facility in San Francisco, USA, for HIV-infected people (5). All 12 M. tuberculosis isolates shared a single IS6110 fingerprint, confirming the authors' expectation that the cases were attributable to the recent transmission of the pathogen in the institutional setting. While this study suggested that TB could both spread rapidly and progress rapidly to active disease in people infected with HIV, many subsequent molecular studies documented the transmission and progression of TB among immunocompetent people as well (6, 7). Shortly after the San Francisco outbreak, Godfrey-Faussett et al. reported the clustering of two M. tuberculosis isolates taken from neighbours with active tuberculosis (8). This was a further demonstration of the concordance between molecular data and the results of conventional contact studies. …

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