TUBERCULOSIS

Mycobacterium tuberculosis

2 billion people have Tuberculosis (TB), mostly in the developing world. But only 10% of cases are aware of it. Clearly the immune system does a pretty good job at containing it, and we call this quiet period of TB the latent phase. If the immune system becomes debilitated down the road (eg, AIDS or old age), then the TB can enter the active phase. The active phase is deadly and contagious. The main risk factor is overcrowding (eg, prison, homeless shelters). 

As a member of the Mycobacteria family, Tuberculosis has some unusual qualities. Whereas most bacterial infections have a simple and acute timeline, the course of a TB infection is convoluted. It’s a slow growing bug, but it’s unusually sneaky. It is adept at avoiding the immune system.

And perhaps more than any other disease, Tuberculosis has a lot of historical importance, but I’ll leave that up to you to look up in your free time (ha!). Instead, I’ll first talk about the course of the infection. 

1. TB is inhaled, and enters the alveoli. 

2. Dust cells (macrophages in the alveoli) eat the TB, and put them into phagosomes. 

3. Normally the macrophage would fuse a lysosome with the phagosome, bringing digestive enzymes into contact with the bacteria. However, TB uses Sulfatides to prevent lysosomes from fusing with the phagosome. So the TB lives on inside the macrophage and replicates in the bottom of the lung. 

4. Cord Factor, a virulence factor on TB, turns TB into  a snake-shape. This is *critical* to ensure virulence -- studies have shown that TB lacking Cord Factor is harmless. CF works by irritating the macrophages, encouraging release of TNFa which recruits more macrophages which work together to form a granuloma. 

5. Thanks to TNFa, a lot of macrophages arrive. They form a perimeter around the TB, and this blob is called a granuloma. In TB, granulomas are filled with necrotic debris inside, which is called a caseating granulomas. Caseating granulomas are filled with cheese-like gunk. The initial cluster of granulomas is called a Ghon focus. It can spread to the hilar lymph nodes, at which point the whole thing is called a Ghon complex. It can also become calcified or fibrosed (Ranke Complex). Confusing! But the nomenclature isn’t frequently tested, hallelujah! At this point, PRIMARY TUBERCULOSIS has begun. Most people are asymptomatic, prodromal or have some pneumonia symptoms. 

   1. 1. 1. 1. 1. Sometimes the Primary TB is totally eradicated, yay

               2. Sometimes the Primary TB immediately overwhelms the entire body, which happens with the immunocompromised, for example with AIDS or with TNFa-inhibitor therapy (commonly used for Inflammatory Bowel Disease). This is PROGRESSIVE PRIMARY TB. The TB spreads like wildfire to every organ. This is also called Miliary TB, which gets its name because the small metastatic TB clusters that spread across the body apparently resemble millet seeds. The meninges, lungs, lymph nodes, liver, spleen, kidneys and bones are all vulnerable to seeding. If the vertebrae are infected, this is called Pott disease (for some reason, this pops up on test questions).  Swollen neck lymph nodes in TB are called scrofula.

               3. But, usually the Primary TB enters a LATENT PHASE. The TB sleeps away inside the granulomas within the lung. There are no symptoms, and the chest x-ray looks normal. Importantly, the PPD test will be positive, but I’ll get to that in a second. Latent TB is treated with a single RIPE antibiotic for several months, often Isoniazid.

                  1. • If the immune system becomes weak (eg, AIDS, old age, started on a TNFa-inhibitor), the TB can leave the latent phase and enter the active phase. SECONDARY TUBERCULOSIS begins.  Cavitary lung lesions will form at the apex of the lung, where there is the most air (TB has aerobic metabolism). It predominantly  remains in the lungs, causing hemoptysis, cough, dyspnea and B symptoms, but Miliary TB can also occur. Active TB is highly infectious, and patients have to be contained in negative pressure rooms if they come into the hospital. 

Purified Protein Derivative (PPD) is a common screening test for TB. You put some TB in a blender, and then inject some of the chopped up protein bits into someone's forearm. If a patient has ever had Primary TB, then the killer T-cells  will recognize the protein. They start an inflammatory response, and after 2 - 3 days redness and induration appear on the forearm. This is an example of a Type 4 Hypersensitivity. It’s a cumbersome test with mediocre sensitivity / specificity though (keep in mind that in AIDS, they may be unable to mount an immune response). Interferon Gamma Release Assays (IGRAs) are a newer, more convenient blood test with better predictive values. If a screening test is positive, then you get a chest x-ray, looking for any active lung lesions. Once you think this is TB, get a bronchiolar lavage sample (or just a sputum sample) which can be sent to the lab for staining, cultures and PCR testing.