Mycobacterial antigens accumulation in foamy macrophages in murine pulmonary tuberculosis lesions: Association with necrosis and making of cavities.

Understanding mechanisms of cavitation in tuberculosis (TB) is the missing link that could advance the field towards better control of the infection. Descriptions of human TB suggest that postprimary TB begins as lipid pneumonia of foamy macrophages that undergoes caseating necrosis and fragmentation to produce cavities. This study aimed to investigate the various mycobacterial antigens accumulating in foamy macrophages and their relation to tissue destruction and necrosis. Pulmonary tissues from mice with slowly progressive TB were studied for histopathology, acid-fast bacilli (AFB) and presence of mycobacterial antigens. Digital quantification using Aperio ImageScope was done. Until week 12 postinfection, mice were healthy, and lesions were small with scarce AFB and mycobacterial antigens. Colony-forming units (CFUs) increased exponentially. At week 16-33, mice were sick, macrophages attained foamy appearance with an increase in antigens (P < .05), 1.5 log increase in CFUs and an approximately onefold increase in AFB. At week 37-41, mice started dying with a shift in morphology towards necrosis. A >20-fold increase in mycobacterial antigens was observed with only less than one log increase in CFUs and sevenfold increase in AFB. Secreted antigens were significantly (P < .05) higher compared to cell-wall antigens throughout infection. Focal areas of necrosis were associated with an approximately 40-fold increase in antigen MPT46, functionally active thioredoxin, and a significant increase in all secreted antigens. In conclusion, mycobacterial antigens accumulate in the foamy macrophages in TB lesions during slowly progressive murine pulmonary TB. Secreted antigens and MPT46 correlated with necrosis, thereby implying that they might trigger the formation of cavities.

Cause of death in patients with tuberculosis: A study based on epidemiological and autopsy records of Western Norway 1931-47.

BACKGROUND: Without treatment, nearly 50 % of tuberculosis (TB) patients die. World Health Organization's definition of TB deaths does not take into consideration whether the cause of death was TB or other non-TB co-morbid conditions. We aimed to improve our knowledge of the causes of death in patients with TB. METHODS: Single-center retrospective study conducted at Gade Institute of Pathology, Haukeland University Hospital, Bergen, Norway. Autopsy data of 269 patients with TB was collected from autopsy journals, and epidemiological data was collected from Norwegian Official Statistics books for period 1931-1947. RESULTS: Of all TB deaths reported in epidemiological reports, pulmonary TB accounted for 81 % and extrapulmonary TB for 19 %. However, in autopsy records, only 21 % of cases with active pulmonary TB died because of TB. Extrapulmonary involvement was significantly associated with higher mortality (OR EPTB as compared to PTB; 3.27, CI 1.91 - 5.61) and constituted 79 % of deaths attributable to TB. A significant burden of extrapulmonary TB was found in autopsy records (63 %), while in epidemiological records, only 4 % of cases were reported. CONCLUSIONS: Extrapulmonary involvement was a predictor of mortality due to TB in hospitalized TB patients. The contribution of extrapulmonary TB to TB mortality seems to be underestimated because extrapulmonary TB largely remains underdiagnosed and underreported in epidemiological data.

Novel Insights into the Pathogenesis of Human Post-Primary Tuberculosis from Archival Material of the Pre-Antibiotic Era, 1931-1947.

OBJECTIVES: Primary and post-primary tuberculosis (TB) are distinct entities. The aim of this study was to study the histopathology of primary and post-primary TB by using the unique human autopsy material from the pre-antibiotic era, 1931-1947. MATERIAL AND METHODS: Autopsy data were collected from the autopsy journals, and the human tissue was collected from the pathology archives at the Department of Pathology, the Gades Institute. RESULTS: Histological presentations of TB lesions showed great diversity within a single lung. Post-primary TB starts as a pneumonia forming early lesions, characterized by the infiltration of foamy macrophages containing mycobacterial antigens within alveoli, and progressing to necrotic pneumonias with an increasing density of mycobacterial antigens in the lesions. These necrotic pneumonic lesions appeared to either resolve as fibrocaseous lesions or lead to cavitation. The typical granulomatous inflammation, the hallmark of TB lesions, appeared later in the post-primary TB and surrounded the pneumonic lesions. These post-primary granulomas contained lesser mycobacterial antigens as compared to necrotic pneumonia. CONCLUSIONS: Immunopathogenesis of post-primary TB is different from primary TB and starts as pneumonia. The early lesions of post-primary TB may progress or regress, holding the key to understanding how a host can develop the disease despite an effective TB immunity.