Tuberculosis as a three-act play: A new paradigm for the pathogenesis of pulmonary tuberculosis

Abstract

Lack of access to human tissues with untreated tuberculosis (TB) has forced generations of researchers to use animal models and to adopt a paradigm that granulomas are the characteristic lesion of both primary and post primary TB. An extended search of studies of human lung tissues failed to find any reports that support this paradigm. We found scores of publications from gross pathology in 1804 through high resolution CT scans in 2015 that identify obstructive lobular pneumonia, not granulomas, as the characteristic lesion of developing post-primary TB. This paper reviews this literature together with other relevant observations to formulate a new paradigm of TB with three distinct stages: a three-act play. First, primary TB, a war of attrition, begins with infection that spreads via lymphatics and blood stream before inducing systemic immunity that contains and controls the organisms within granulomas. Second, post-primary TB, a sneak attack, develops during latent TB as an asymptomatic obstructive lobular pneumonia in persons with effective systemic immunity. It is a paucibacillary process with no granulomas that spreads via bronchi and accumulates mycobacterial antigens and host lipids for 1-2 years before suddenly undergoing caseous necrosis. Third, the fallout, is responsible for nearly all clinical post primary disease. It begins with caseous necrotic pneumonia that is either retained to become the focus of fibrocaseous disease or is coughed out to leave a cavity. This three-stage paradigm suggests testable hypotheses and plausible answers to long standing questions of immunity to TB.

Keywords: Cavity; Human; Lung; Pathogenesis; Pathology; Post primary.

Figure 1. Characteristic pathologies of human post-primary TB from the 19^th and 21^st centuries

Each pair of figures shows a drawing from the 19^th century paired with a 21^st century photomicrograph. The caseating granuloma is the characteristic lesion of primary TB. Post-primary TB begins a paucibacillary lobular pneumonia (Acute) that may undergo caseous necrosis (Acute Caseating), regress (Subacute Dry) or fibrose (Chronic Fibrosing). Finally, caseating granulomas in post-primary TB form only in response to caseous necrosis and are never the cause of it (Post-primary Granuloma). The first 5 drawings are by Cornil and Ranvier (1881) , The last one is by Hamilton (1883) . The sections are H&E or trichrome stained and photographed at 40 to 400×.

Figure 2. Histopathology of formation of cavities in the 19^th and 21^st centuries

The caption of this drawing of a developing tuberculous cavity by Hamilton in 1883 stated: “The cavity formed by dissolution of the center of a caseous pneumonic mass” . The sections from persons who died recently of acute tuberculous pneumonia show the same pathology. Tuberculous pneumonia has undergone caseation necrosis, fragmentation and is being coughed out to form a cavity. The larger section shows necrotic lung above tuberculous pneumonia (H&E 40×).

Figure 3. Bronchial obstruction in developing post-primary TB

The tree-in-bud sign is a high definition CAT scan of the characteristic lesion of developing post-primary TB (upper left). It is an image of a pulmonary lobule with obstructed bronchioles and alveoli filled with cells and fluids (upper center). It was named for resemblance to a tree twig with buds (upper right). The identification of this lesion as the earliest stage of post-primary TB and its histology have been reported consistently since the 1880’s. Hamilton’s drawing and the flanking photomicrographs show the characteristic lobular obstruction and the associated lobular infiltration with mononuclear cells. Drawing reproduced from Hamilton (H&E Stains 200×).

Figure 4. Tree-in-bud sign marking advancing cavitary TB

A 4-mm coronal CT maximum intensity projection image. The black arrows point to nodules in the right upper and left lower lobes of the lungs, with a “tree-in-bud” appearance due to small airway spread of tuberculous infection. The large left upper lobe cavity (red arrow) is a hallmark of postprimary TB. The accompanying loculated left-sided tuberculous empyema (orange arrow) was subsequently drained percutaneously. Reproduced from Marshall et al .

Figure 5. MTB antigen in alveolar cells of immunocompetent people

A. Immunohistochemical stain using polyclonal antibody against MTB in alveolar macrophages in lobular pneumonia of an immunocompetent person with developing post-primary TB (IHC Stain 200×). B. Higher power of same section showing that the antigen is entirely intracellular. (IHC 1000×). AFB stain of these sections showed no organisms demonstrating a paucibacillary infection. The antigen staining is entirely intracellular until onset of necrosis. Reproduced from Hunter .

Figure 6. Tuberculosis as a Three Act Play

The current paradigm of the pathogenesis of TB considers TB to a one act play in which the caseating granuloma modulated by CMI is the characteristic lesion of all TB. While this is an appropriate model for M. bovis and the early stages of post-primary TB, it fails to recognize the existence of obstructive lobular pneumonia that initiates and drives all of post-primary TB.