Tuberculosis: Pathology review

Definitions & Key takeaways

Tuberculosis (TB) is a chronic infectious disease caused by the bacterium Mycobacterium tuberculosis. The pathophysiology of TB involves a complex interplay between the bacterium and the immune system of the host. When a person inhales air contaminated with M. tuberculosis, the bacteria can enter the lungs and infect the alveolar macrophages, which are the immune cells responsible for clearing foreign particles from the lungs. In most cases, the immune system can contain the infection and prevent the development of active TB disease.

However, in some cases, the bacteria can evade the immune system and establish a latent infection, in which the bacteria remain dormant in the body for years or even decades. Latent TB infection is not contagious and does not cause symptoms, but it can progress to active TB disease if the immune system becomes weakened, such as in people with HIV/AIDS, malnutrition, or other conditions that compromise the immune system.

In active TB disease, the bacteria can multiply and spread throughout the body, causing symptoms such as cough, fever, weight loss, and night sweats. The infection can also damage the lungs and other organs, leading to complications such as pleural effusion, pneumonia, and meningitis.

Chapters:

Watch video only

Case Study0:00–0:45

While doing your rounds, you meet Josh, an HIV-positive 25-year-old man who presents with a 2-month history of non-productive cough.
He also describes poor appetite and significant weight loss, fever, night sweats, and excessive tiredness. He denies dyspnea or hemoptysis.
Physical examination is unremarkable. A PPD intradermal test was performed and it was negative.
His chest X-ray showed a peri-hilar lesion with central necrosis and calcification as well as lymphadenopathy of nearby nodes.

Microbiology0:45–1:49

Now, this person seems to suffer from tuberculosis, or TB for short. But first, a bit of microbiology.
Mycobacteria tuberculosis are slender, rod-shaped, Gram positive bacteria that need oxygen to survive, in other words, they’re “strict aerobes”.
One piece of high-yield information is that although they are classified as Gram positive - meaning they have an outer cell wall, it is the same wall that makes the bacteria special.
This is because Mycobacterium have an unusually waxy cell wall made of mycolic acid, which is composed of long chains of branched lipids, which won't stain with Gram.
This makes them “acid-fast” so the Ziehl-Neelsen stain has to be applied, a dye that will not be washed away by acids, giving the bacteria a bright red color.
The wall also makes the bacteria incredibly hardy, and allows them to resist weak disinfectants, antibiotics, and allow them to survive on dry surfaces for months at a time.
Okay, so Tuberculosis is a type of pulmonary infection caused by Mycobacterium tuberculosis, sometimes just called TB bacteria.

Risk Factors1:49–2:36

Before we start, you need to know that there are a few high-yield risk factors for TB. These include immunosuppression, like in people with HIV; iatrogenic immunosuppression, like in people who undergo treatment with corticosteroids; systemic diseases such as COPD, diabetes, and end-stage renal disease; extremes of age; substance abuse; and populations with an increased risk of exposure, like the prison populations, homeless people, those born in an endemic country, and health care workers.Okay, so let’s start by talking about primary tuberculosis.

Primary Tuberculosis2:36–6:30

This is where TB bacteria are transmitted when a person breathes in contaminated aerosolized droplets coughed up by someone who has TB.
This is not normally a problem, as we have plenty of defense mechanisms against the microorganisms we inhale. They are often trapped in the mucus secretions in the upper respiratory tract and coughed up.
TB that make it to the alveoli are phagocytized by macrophages, where they are trapped inside phagosomes, that later fuse with a hydrolytic enzyme-containing lysosome that normally breaks down harmful microbes.
However, TB bacteria can survive this process due to sulfatide, a surface protein that inhibits the phagosome-lysosome fusion.
So, what you need to know is that this allows the mycobacterium to survive, proliferate inside the macrophage, and cause a localized infection within one week of exposure.
However, most people at this stage are actually asymptomatic and unaware they are infected because the immune system can contain the bacteria quite efficiently.
However, around 3 weeks after initial infection, a surface glycolipid called TB cord factor triggers an immune response where numerous cytokines are released, attracting more macrophages and helper T-cells to the area.
They try to quarantine the TB bacteria by forming granulomas. Remember that this granuloma formation is a cell-mediated type IV hypersensitivity reaction where helper T-cells presented with TB antigen activate, and release cytokines that attract more macrophages to the area.
These macrophages, dead tissue, and bacteria form the center of the granuloma, while helper T-cells and multinucleated giant cells, which are formed by the fusion of several macrophages, are found on the periphery.
These giant cells, called Langhans giant cells are very high yield. Their multiple nuclei are arranged peripherally, resembling the shape of a horseshoe.
Their cytoplasm contains Schaumann bodies which are made of calcium and protein deposits, and abnormal lipid structures called asteroid bodies.
Now, in tuberculosis, granulomas are usually caseating. This is because the tissue in the middle of the granuloma dies as a result of a process called caseous necrosis, which means “cheese-like” necrosis, since the dead tissue is soft, white, and resembles cheese.
These areas are known as a “Ghon focus”. Now, TB can also spread to nearby hilar lymph nodes, either carried over by immune cells through the lymphatic system or by direct invasion from the Ghon focus.
Together, the Ghon focus and the affected lymph node, form the “Ghon complex,” which is characteristic of primary tuberculosis.
A high yield fact is that Ghon complexes are usually subpleural and occur in the mid and lower lobes of the lungs. From here on, there are a few possible outcomes.
In children and immune compromised individuals, primary tuberculosis can not be contained by granulomas so they spread throughout the lungs, causing further damage.
This is called progressive primary tuberculosis. In most cases however, the tissue that’s encapsulated by the granuloma undergoes fibrosis, and often calcification, producing scar tissue that can be seen on x-ray.
A calcified ghon complex is called a “Ranke complex”. In some cases, the mycobacteria is killed off by the immune system and the complex heals, leaving just a small scar behind, and that’s the end of that.

Secondary Tuberculosis6:30–7:53

However, if the TB bacteria in the Ghon complex isn’t eliminated, we can get secondary tuberculosis. Even though the bacteria are walled off, they remain viable but latent.
If and when a person’s immune system becomes compromised, the Ghon complex can become reactivated, and the infection can spread throughout the lung parenchyma.
Another high-yield fact is that the infection usually spreads to either one or both upper lobes of the lung, mostly because oxygenation is greatest in these areas, and TB being an aerobe, prefers areas of greater oxygenation.
Now, since individuals were previously exposed to the bacteria, the immune system’s memory T cells quickly release cytokines to try and control the new outbreak, which forms more areas of caseous necrosis and more lung parenchyma is destroyed.
If the damage is severe, it could cause fibrocaseous cavities. Because the cavities are large, they can allow the bacteria to disseminate, or spread, through airways and lymphatic channels to other parts of the lungs, causing bronchopneumonia.
Another way the infection in both secondary and progressive primary tuberculosis can spread is via the vascular system, causing bacteremia.
This way, TB can infect almost every other tissue in the body, leading to systemic miliary TB.When TB spreads to other tissues, it causes complications related to the organ affected.

Symptoms7:53–9:12

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.
It can also spread to the joints, where it causes mycobacterial arthritis, and long bones, where it leads to osteomyelitis.Now, the symptoms of pulmonary tuberculosis are varied, depending on the phase of the disease and any comorbidities.
Primary tuberculosis might be completely asymptomatic, or it might present with classic findings, including fever, night sweats, weight loss, non-productive and productive cough, and hemoptysis, usually secondary to the infection eroding the pulmonary blood vessels.
Secondary tuberculosis will have similar symptoms, and miliary tuberculosis might cause additional symptoms, depending on which organs are affected.

Diagnosis9:12–12:22

Screening 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, a component of the bacteria, is injected between the layers of the dermis. If a person has previously been exposed to TB, the immune system reacts to tuberculin and produces a small, localized type IV hypersensitivity reaction within 48 to 72 hours; if the reaction creates a large enough area of induration rather than just redness, the test is positive.
However, a positive tuberculin test simply means the individual has been exposed to the TB bacteria at some point. It doesn’t differentiate between active, latent or resolved infections, hence why it is a screening test and not diagnostic.
PPD is negative when there’s no history of infection. There’s also the chance of false positive results in those who were vaccinated against TB, and of false negative results when the immune system is too impaired to even react to tuberculin, like in individuals with AIDS.
Sarcoidosis can also lead to false negative results because the affected individuals have impaired delayed-type immune reactions.
As an alternative screening test, there are also interferon gamma release assays, or IGRAs. Basically, they work by measuring the amount of interferon-gamma released by T-lymphocytes when exposed to antigens unique to Mycobacterium tuberculosis.
IGRAs are more specific to TB rather than other types of mycobacterial infections and are less likely to give a false positive result.
If any of the two tests were positive and the individual presents characteristic symptoms, the next step is a chest Xray to look for signs of active TB disease.
Ghon complex with calcification is a classic sign of TB, but cavitation and scarring in the upper lobes are more suggestive of secondary TB.
Miliary tuberculosis, on the other hand, can cause numerous small nodules that are uniform in size and distributed throughout the lungs.
In fact “Miliary” refers to the millet seeds that these nodules resemble. If chest radiography was positive, it’s important to collect three samples of sputum at least eight hours apart and including at least one early-morning specimen, or alternatively, by bronchoalveolar lavage.
These samples are sent to the lab for staining, culture on Lowenstein Jensen agar, and nucleic acid amplification test to look for evidence of mycobacterium tuberculosis.
A biopsy of the nodule might also be beneficial, which can reveal caseating granulomas with central necrosis and Langhans giant cells.Now, let’s look at treatment.

Treatment12:22–17:27

For latent TB infection, it typically involves using monotherapy with rifamycin for four months. This is now preferred over monotherapy with isoniazid for 9 months, which used to be the number one option.
Monotherapy with isoniazid for 9 months is still though the only regimen used as prophylaxis against TB in those at risk of developing the disease, especially in individuals with HIV.
Treatment of active TB disease is typically done through a combination of anti-TB antibiotics, called the RIPE regimen and which consists of rifampin, isoniazid, pyrazinamide, and ethambutol; streptomycin can also be added to the initial regimen if necessary, otherwise it is considered a second line solo agent.
There are a few other things you need to know for your exams about these antibiotics. First, rifampin works by blocking the bacteria from synthesizing DNA-dependent RNA, thereby preventing transcription.
And with no way of generating mRNA, the bacteria will die. This mechanism allows it to work on a wide range of bacteria, not just TB, the only downside being that if the bacteria develops a mutation that changes the enzyme responsible for DNA-dependent RNA synthesis, it will develop bacterial resistance to rifampin.
Some side-effects include minor hepatotoxicity and drug interactions, and, something less serious, orange body fluids. Second, isoniazid acts by inhibiting mycolic acid synthesis, meaning it works only on TB.
However, isoniazid needs to be processed by the mycobacterial catalase-peroxidase to be activated. So, if TB develops a mutated gene that results in the non-expression of the catalase-peroxidase enzyme or if it acquires a mutation that modifies the isoniazid binding site on the mycolic acid synthesis enzyme, the bacteria can develop resistance against isoniazid.
Some of its side effects include hepatotoxicity, P- 450 inhibition, drug-induced lupus, anion gap metabolic acidosis, and seizures that are refractory to benzodiazepines.
Now, it can also cause vitamin B6 deficiency, which can lead to peripheral neuropathy and sideroblastic anemia. This is why isoniazid is administered at the same time with pyridoxine which is B6 vitamin.
Third, pyrazinamide has an unknown mechanism but it works best at relatively acidic pHs, as within phagolysosomes, which is why it is the most efficient against the TB engulfed by macrophages.
Pyrazinamide can cause hyperuricemia and hepatotoxicity. Fourth, ethambutol inhibits arabinosyl transferase, an enzyme that polymerizes a part of the bacterial cell wall.
Without this enzyme to promote carbohydrate polymerization, TB dies since it can’t build its cell wall. Ethambutol doesn't work on other microorganisms, but it can be used to treat atypical mycobacterial infections.
It also requires periodic visual acuity testing as it can lead to optic neuritis, which is inflammation that damages the optic nerve.
Optic neuritis leads to symptoms like decreased visual acuity, color blindness, and blind spots, all of which are reversible if the drug is stopped.
And finally, streptomycin is part of the aminoglycoside family, and it works by inhibiting the bacteria’s 30s ribosomal component, ultimately preventing bacterial protein synthesis.
Obviously, mutations to these bacterial ribosomal proteins cause streptomycin resistance, which is actually quite common since this agent was one of the first antibiotics to treat tuberculosis effectively.Additionally, there’s an enormous concern 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 XDR-TB which is Extremely drug resistant TB, both of which are incredibly hard to treat because they don’t respond to treatment with the usual antibiotics.
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.
Alright, as a quick recap. Tuberculosis is an infection caused by Mycobacterium tuberculosis, that mainly affects the lungs.

Review17:27–19:31

Primary TB is when lung infection occurs after inhaling contaminated respiratory droplets. The immune system tries to contain the infection by creating granulomas and the tissue in the center can undergo caseous necrosis, resulting Ghon focus.
TB also extends to nearby hilar lymph nodes, and together with Gohn’s focus they form Ghon complex. If the immune system becomes compromised, like with AIDS, or older age, Ghon focus can reactivate, and the infection can spread to one or both upper lobes of the lungs, where it forms cavities.
From these, 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 individuals with fevers, night sweats, weight loss, and hemoptysis, a sputum sample can be used to identify Mycobacterium tuberculosis.
Treatment of active TB includes a combination of antibiotics called the RIPE regimen.Now, back to our case. Josh is a textbook case of tuberculosis.
His history of HIV infection is a risk factor and he presents with non-productive cough, significant weight loss, fever, and night sweats.
The screening via the PPD intradermal test was negative but this might be due to a diminished response due to HIV. His chest X-ray showed a Gohn complex though, so the next step would be to start him on

Summary19:31–19:28

Tuberculosis: Video, Causes, and Symptoms | Osmosis