The Pathogenesis of Tuberculosis–The Koch Phenomenon Reinstated
The paradigm that granulomas are the hallmark of TB is a product of animal research of the late 20th century when human tissues were no longer available to most investigators. Careful study of human lung tissue with developing post-primary TB (PPTB) together with extensive review of the literature on the pathology, immunology and clinical course of TB in the preantibiotic era produced a more nuanced conception of the pathogenesis of PPTB. TB in man produces two types of granulomas only one of which is studied in animal models. Primary granulomas occur in many species and are widely studied. Post-primary granulomas, in contrast, occur naturally only in human lungs and are seldom studied even though they have a distinctive structure and account for 80% of all cases of clinical TB. Post-primary granulomas develop to surround retained foci of caseous pneumonia. This caseous pneumonia develops from a subclinical infiltrate, the Assman focus, typically in an upper lobe. Its distinctive appearance on X-ray has been described for a century with the terms “studding of bronchi”, “budding twigs,” “raisins on a stem” or “pussy willows. Today it is recognized on CT scans as the ‘tree in bud’ sign that is characteristic of developing PPTB. Histologically, it is an obstructive lobular pneumonia that spreads via bronchi. It begins as the early lesion; a prolonged subclinical stockpiling of secreted mycobacterial antigens in foamy alveolar macrophages and nearby highly sensitized T cells in preparation for a massive necrotizing hypersensitivity reaction, the Koch Phenomenon, that produces caseous pneumonia that is either coughed out to form cavities or is retained to become the focus of post-primary granulomas and fibrocaseous disease. This revised paradigm is supported by nearly 200 years of research and suggests new approaches and animal models to investigate long standing mysteries of human TB and vaccines that inhibit the early lesion to finally end its transmission.