Tuberculosis in children and adults: two distinct genetic diseases

Abstract

Disseminated disease in children and pulmonary disease in adults constitute two major epidemiological and clinical forms of tuberculosis. Paradoxically, only a small fraction of infected individuals develop clinical tuberculosis, typically one form of the disease or the other. Mendelian and complex genetic predispositions to tuberculosis were reported recently in children and adults, respectively. Here, we argue that tuberculosis and its clinical expression largely reflect the underlying human genetic background.

Figure 1.

Mortality rates for disseminated tuberculosis (blue bars) and chronic pulmonary tuberculosis (red bars) per 100,000 untreated persons of various ages living in Bavaria in 1905 (adapted from references and 28). Note that there were too few deaths to accurately plot cases of pulmonary tuberculosis before the age of 20 and disseminated tuberculosis between the ages of 5 and 20 yr. These data relate to the natural history of tuberculosis in an endemic area before BCG vaccines and antimycobacterial antibiotics were available. Vaccination against and early diagnosis and treatment of tuberculosis in children may now have blurred the corresponding clinical phenotypes of tuberculosis, but not the underlying genotype. There are other forms of tuberculosis, with primary infection in adults and reactivation in late childhood. There is, however, clearly a “golden age” between the ages of 4 and 13 yr (reference 6).

Figure 2.

Bayesian estimation of the rate of Mendelian predisposition to disseminated tuberculosis in childhood in endemic areas. The x axis corresponds to P(Mendel), the y axis corresponds to P(cTB/Mendel), and the z axis corresponds to P(Mendel/cTB) (see “Bayesian estimation of the frequency…”). As an example, assuming P(Mendel) = 0.0001 and P(cTB/Mendel) = 0.5, the estimated proportion of Mendelian cases among children with disseminated tuberculosis is P(Mendel/cTB) = 0.25.