Tuberculosis – causes, symptoms, diagnosis, treatment & pathology

Tuberculosis – causes, symptoms, diagnosis, treatment & pathology


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 remains 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 to survive, 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
it 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 in 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 virus and bacteria all the time, but we’ve got defenses that take care
of most of them. For one, 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 which 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. With 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 nearby 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 is 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 Pott 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 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 Xray to look for signs of active TB disease. In
patients with symptoms like as fevers, night sweats, weight loss, and 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 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 a combination of antibiotics,
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.

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