Leukemia (Blood Cancer)

Tuberculosis  

            It’s estimated that about two billion people worldwide are infected with mycobacterium tuberculosis, often just shortened to tuberculosis or simply ‘TB’. Two billion is a ton of people, but even though they’re infected, that doesn’t mean all those people have symptoms, the vast majority, about 90-95%, aren’t even aware they’re infected. And this is because usually, the immune system can contain it such that it isn’t able to multiply, and often remain latent, or dormant, as opposed to active, which usually causes symptoms and can be spread to others.

If the host’s immune system becomes debilitated at some point down the road, like with AIDS or some other illness, or as a person grows older, it can be allowed to reactivate, or basically wake up and become very serious, especially if it spreads through the body. Mycobacteria are an interesting bunch, they’re slender, rod-shaped, and need oxygen in other words; they’re “strict aerobes”. They’ve got an unusually waxy cell wall, which is mainly a result of the production of mycolic acid.

Because of this waxy cell wall, they’re “acid-fast”, meaning that they can hold on to a dye in spite of being exposed to alcohol, leaving it bright red colored when a Ziehl– Neelsen stain is used. The wall also makes them incredibly hardy and allows them to resist weak disinfectants and survive on dry surfaces for months at a time. Now Mycobacterium tuberculosis is usually transmitted via inhalation, which is how they gain entry into the lungs. Now, we breathe in all sorts of viruses and bacteria all the time, but we’ve got defenses that take care of most of them.

For one, the air that we breathe in is turbulent in the upper airways and drives most bacteria against mucus which is then cleared pretty quickly. Ultimately, though, TB can avoid the mucus traps and make its way to the deep airways and alveoli where we have macrophages that eat up foreign cells, digest and destroy them. With TB, they recognize foreign proteins on their cell surface, and phagocytize them, or essentially package them into a space called a phagosome. In most cases, the macrophage then fuses the phagosome with a lysosome, which has hydrolytic enzymes that can pretty much break down any biochemical molecule. TB’s tricky, though, and once inside the macrophage, they produce a protein that inhibits this fusion, which allows the mycobacterium to survive.

It doesn’t just survive, though, it proliferates and creates a localized infection. At this point, somebody has developed primary tuberculosis, which means that they have signs of infection soon after being exposed to TB. Even though it sounds bad, most people at this stage are actually asymptomatic or maybe have a mild flu-like illness. About 3 weeks after initial infection, cell-mediated immunity kicks in, and immune cells surround the site of TB infection, creating a granuloma, essentially an attempt to wall off the bacteria and prevent it from spreading. The tissue inside the middle dies, as a result, a process referred to as caseous necrosis, which means “cheese-like” necrosis, since the dead tissue is soft, white, and looks a bit like cheese. This area is known as a “Ghon focus”. TB also gets to hilar lymph nodes, either carried over by immune cells through the lymph or by direct extension of the Ghon focus infection and causes caseation there as well, and together, this caseating tissue and associated lymph node make up the characteristic “Ghon complex”.

Ghon complexes are usually subpleural and occur in the lower lobes of the lungs. The tissue that’s encapsulated by the granuloma undergoes fibrosis, and often calcification, producing scar tissue that can be seen on x-ray, this calcified ghon complex is called a “Ranke complex”. In some cases, although a scar is leftover, the mycobacteria are killed off by the immune system, and that’s the end of that. In other cases, even though they were walled off, they remain viable and are therefore still alive, but they’re just dormant. If and when a person’s immune system becomes compromised, like with AIDS or with aging, the Ghon focus can become reactivated, and the infection can spread to either one or both upper lobes of the lungs, it’s thought that this is because oxygenation is greatest in these areas, and TB being an aerobe, prefers areas of greater oxygenation.

Since they were previously exposed, the immune system’s memory T cells quickly release cytokines to try and control the new outbreak, which forms more areas of caseous necrosis, this time, though, it tends to cavitate, or form cavities, which can allow the bacteria to disseminate, or spread through airways and lymphatic channels to other parts of the lungs, which can cause bronchopneumonia; but it can also spread via the vascular system and infect almost every other tissues in the body, called systemic miliary TB. When TB spreads to other tissues, it causes complications related to the organ affected. Kidneys are commonly affected, resulting in sterile pyuria, or high levels of white blood cells in the urine. It might also spread to the meninges of the brain, causing meningitis, the lumbar vertebrae, causing Potts disease, the adrenal glands causing Addison's disease, the liver causing hepatitis, and the cervical lymph nodes causing lymphadenitis in the neck, also known as scrofula. 

Testing for TB often starts with a purified protein derivative or PPD intradermal skin test, sometimes known as a tuberculin skin test, Mantoux test, or simply TB test. With this test, tuberculin is injected between layers of the dermis, tuberculin is a component of the bacteria, and if a person has previously been exposed to TB, the immune system reacts to the tuberculin and produces a small, localized reaction within 48 to 72 hours; if the reaction creates a large enough area of induration (rather than just redness), it’s considered to be a positive test. Positive tuberculin tests simply mean the patient’s been exposed at some point to TB—it doesn’t differentiate between active and latent disease.

As an alternative to tuberculin skin tests, there are also interferon-gamma release assays (or IGRAs) which look for evidence in the blood of previous exposure to TB proteins. Since this one’s a blood test, you don’t need to show up again to have the test read like you do with the PPD. Also, the IGRA is more specific to TB rather than other types of mycobacterial infections and is unlikely to be positive as a result of having BCG vaccine in the past, a vaccine that protects against TB. And this is a pretty useful feature of IGRAs since the BCG vaccine is given to many children around the world to prevent disseminated TB. After doing a screening test with PPD or IGRA, anyone with a positive result typically gets a chest X-ray to look for signs of active TB disease.

In patients with symptoms like fevers, night sweats, weight loss, coughing up blood, or hemoptysis. it’s important to collect samples from either the sputum, or via a bronchoalveolar lavage, which is where a bronchoscope is inserted through the mouth or nose into the lungs, fluid is squirted, and then the fluid is collected. These samples can get sent to the lab for staining, culture, and PCR to look for evidence of mycobacterium tuberculosis. Treatment of latent TB infection typically involves using a single drug for a prolonged period of time—the most common approach is Isoniazid for 9 months. Treatment of active TB disease is typically done with different combinations of anti-TB antibiotics, like isoniazid, rifampin, ethambutol, and pyrazinamide, which results in patients being non-infectious to others usually within a few weeks. Until that point, though, patients can spread TB to others and it’s typically adults with reactivated TB that are the most infectious.

As a result, patients are typically kept in negative pressure rooms and visitors are asked to wear protective N-95 masks that can’t filter out oil aerosols (N for “not resistant to oil”) but can filter out at least 95% of other aerosols (in this case TB). Even after patients are no longer contagious, they’re typically kept on multiple medications for many months to be sure the bacteria are destroyed usually with directly observed therapy or DOT where somebody watches and confirms that you’re taking the medication. Additionally, there’s an enormous worry about new drug-resistant strains of TB that are causing infections in various parts of the world. You may hear of (MDR-TB or Multi-drug resistant TB) or even (XDR-TB which is extremely drug-resistant TB) which is incredibly hard to treat because they don’t die in the presence of our usual antibiotics.

The bottom line is that to get an effective treatment, it’s super important to make sure that the drugs being used will work against the specific strain of TB, that multiple medications are used together to prevent drug resistance from developing, and that medications are used for the entire course of therapy so that all of the mycobacterium tuberculosis is killed off. Recently, the US Food and Drug Administration has approved a breakthrough medication for XDR-TB, called pretomanid. According to recent studies, a combination of pretomanid, bedaquiline, and linezolid has been effective for almost 90% of XDR-TB cases. As an added bonus, this combination therapy can be taken orally and is also very well tolerated compared with other XDR-TB drug regimens.

Alright, as a quick recap. Tuberculosis, or TB, is an infection caused by Mycobacterium tuberculosis, that mainly affects the lungs. 3 weeks after the primary infection, the immune system tries to contain the infection by creating a granuloma, and the tissue in the middle undergoes caseous necrosis, resulting in an area called Ghon focus. TB also extends to nearby hilar lymph nodes, causing caseous necrosis there as well. Ghon focus plus the affected lymph node make up the characteristic Ghon complex. If the immune system becomes compromised, like with AIDS, or older age, Ghon focus can reactivate, and the infection may spread to one or both upper lobes of the lungs, where it forms cavities. From cavities, bacteria can disseminate to other parts of the lungs, causing bronchopneumonia, but it can also spread through the vascular system and infect almost every tissue in the body, which is called systemic miliary TB. Testing for TB starts with a PPD intradermal skin test, or with an IGRA blood test, and a chest X-ray can identify signs of active TB disease. In patients with fevers, night sweats, weight loss, and hemoptysis, a sputum sample can be stained, cultured and PCR can be done to look for Mycobacterium tuberculosis. Treatment of active TB includes a combination of antibiotics, given for several months, and special regimens are used for MDR-TB and XDR-TB.