Pathogenesis of tuberculosis: pathway to apical localization.

We have examined the published work of investigators which dealt with the pathogenesis of tuberculosis, especially the following: the infective dose, the yield of bacilli from the primary lesion and primary complex, the predominant location of the minimal lesion, the hypotheses of a vulnerable region in the lung and the specific pathways (endogenous or exogenous) by which tubercle bacilli cause disease. More knowledge of the pathogenic pathway to tuberculosis would provide clues to the development of new vaccines and drug regimens that can intervene at a specific stage in the pathogenesis. Based on the examination of the literature on pathogenesis of human tuberculosis and our findings in a guinea-pig model of experimental airborne tuberculosis, we have proposed an hypothesis which integrates the endogenous and exogenous pathways to tuberculosis. This hypothesis is based on the following observations: 1. The infectious dose is very low, usually 1-5 tubercle bacilli. 2. The first implant can occur anywhere in the lungs. 3. The cavitary lesion, characteristic of tuberculous disease, is often located in the apical regions in the lungs. 4. Whereas the primary implant can occur anywhere in the lungs, for the progression from infection to disease, the tubercle bacilli must gain access to the 'vulnerable' regions in the apex of the lungs. Our hypothesis states that in areas of the world where there is a low risk of infection with tubercle bacilli low incidence of vaccination or sensitization to environmental mycobacteria, or high incidence of high virulent isolates, the virulent tubercle bacilli reach the vulnerable region via a bacillemia during the first infection. In areas of the world where there is a high risk of infection with tubercle bacilli, high incidence of vaccination or sensitization to environmental mycobacteria or a high incidence of low virulent isolates, the tubercle bacilli reach the vulnerable region via the airway, which requires repeated episodes of infection as the probability of a first implant occurring in the vulnerable regions is low.