Tuberculosis

It’s estimated that about two billion people worldwide are infected with mycobacterium
tuberculosis, often just shortened to tuberculosis (TB). 2 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 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 coloured 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.

Mycobacterium tuberculosis is usually transmitted via inhalation, which is how they gain entry into
the lungs. We breath in all sorts of virus and bacteria all the time, but we’ve got defences that take
care of most of them. For one, air that we breath 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 it’s 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. With
most cases, the macrophage then fuses the phagosome with 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.

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 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 kind like a cheese. TB also gets to hilar lymph
nodes, either carried over by immune cells through the lymph or by direct extension of the Ghon
focuses 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 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 van also spread via the vascular
system and infect almost every other tissues in the body, called systemic military 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 purified protein derivate (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 71 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
(IGRA) which look for evidence in the blood of previous exposure to TB proteins. Since this one’s a
blood test, it don’t need to show up again to have the test read like 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
an useful feature of IGRA, 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 YB disease. In patients with symptoms like as
fevers, night sweats, weight loss, and coughing up blood (hemoptysis), it’s important to collect
samples from either the sputum, or via 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
done with different combinations of anti-TB antibiotics, like isoniazid, rifampicin, ethambutol and
pyrazinamide. Which results in patients being non-infectious to others usually within a few weeks.
Until the 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. 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 (DOT) where somebody watches and confirms that
you’re taking the medication.
There’s an enormous worry about new drug-resistant strains of TB that are causing infections in
various parts of the world. MDR-TB (multi-drug resistant TB) or even XDR-TB (extremely drug
resistant TB) which is incredibly hard to treat because they don’t die in the presence of 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 (FDA) 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. Combination therapy can be taken
orally, and is also very well tolerated compared with other XDR-TB drug regimens.

Recap

Tuberculosis (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 reactivated, 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 military TB. Testing for TB starts with a PPD intradermal skin test, or with 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, culture 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.
Tuberculosis (TB) is one of the oldest and most common infectious diseases. Tuberculosis is caused
by a rod-shaped bacterium or a bacillus, called Mycobacterium tuberculosis. An infection is initiated
following inhalation of mycobacteria present in aerosol droplets discharged into the atmosphere by
a person with an active infection. The transmission process is very efficient as these droplets can
persist in the atmosphere for several hours and the infectious dose is very low, less than 10 bacilli
are needed to start the infection.

Once in the lung, the bacteria meet the body’s first line defence, the alveolar macrophages. The
bacteria are ingested by the macrophages but manage to survive inside. Internalization of the bacilli
triggers an inflammatory response that brings other defensive cells to the area. Together, these cells
form a mass of tissue, called a granuloma, characteristic of the disease. In its early stage, the
granuloma has a core of infected macrophages enclosed by other cells of the immune system. As
cellular immunity develops, macrophages loaded with bacteria are killed, resulting in the formation
of the caseous center of the granuloma. The bacteria become dormant but may remain alive for
decades. This enclosed infection is referred to as latent tuberculosis and may persist throughout a
person’s life without causing any symptoms. The strength of the body’s immune response
determines whether an infection is arrested here or progresses to the next stage. In healthy people,
the infection may be stopped permanently at this point. The granulomas subsequently heal, leaving
small calcified lesions.

On the other hand, if the immune system is compromised by immunosuppressive drugs, HIV
infections, malnutrition, aging, or other factors, the bacteria can be re-activated, replicate, escape
from the granuloma and spread to other parts of the lungs causing active pulmonary tuberculosis.
This reactivation may occur months or even years after the initial infection.

In some cases, the bacteria may also spread to other organs of the body via the lymphatic system or
the bloodstream. This widespread from of TB disease, called disseminated TB or military TB, occurs
most commonly in the very young, the very old and those with HIV infections.

Tuberculosis is generally treatable with antibiotics. Several antibiotics are usually prescribed for
many months due to the slow growth rate of the bacteria. It’s very important that patients complete
the course of the treatment to prevent development of drug-resistant bacteria and re-occurrence of
the disease.
Tuberculosis (pulmonary
manifestations)
Pulmonary manifestations of tuberculosis are varied and depend in part whether the infection is
primary or post-primary. The lungs are the most common site of primary infection
by tuberculosis and are a major source of spread of the disease and of individual morbidity and
mortality.

A general discussion of tuberculosis is found in the parent article: tuberculosis; and a discussion of

other mycobacterial infections of the lungs is found here: pulmonary Mycobacterium avium complex
(MAC) infections.

Clinical presentation
The primary infection is usually asymptomatic (the majority of cases), although a small number go on
to have symptomatic hematological dissemination which may result in miliary tuberculosis. Only in
5% of patients, usually those with impaired immunity, go on to have progressive primary tuberculosis.

Patients with post-primary pulmonary tuberculosis are often asymptomatic or have only minor
symptoms, such as a chronic dry cough. In symptomatic patients, constitutional symptoms are
prominent with fever, malaise, and weight loss. A productive cough which is often blood-stained may
also be present 1.

Occasionally patients may present with massive hemoptysis due to an erosion of a bronchial artery 1,3.

Clinical presentation in AIDS patients

Patients with AIDS demonstrate altered patterns of infection depending on their CD4 count. When
CD4 count drops to below 350 cells/mm3 pulmonary manifestations appear similar to run-of-the-mill
post-primary infections (see below). When CD4 counts drop below 200 cells/mm 3 then the pattern of
infection is more likely to resemble primary infection or miliary tuberculosis 4. Nodal enlargement is
also common at this stage.
Pathology
Location
The location of infection within the lung varies with both the stage of infection and age of the patient:

 primary infection can be anywhere in the lung in children whereas there is a predilection

for the upper or lower zone in adults 1
 post-primary infections have a strong predilection for the upper zones
 miliary tuberculosis is evenly distributed throughout both lungs

Radiographic features
Radiographic features depend on the type of infection and are discussed separately.

Primary pulmonary tuberculosis

In primary pulmonary tuberculosis, the initial focus of infection can be located anywhere within the
lung and has non-specific appearances ranging from too small to be detectable, to patchy areas of
consolidation or even lobar consolidation. Radiographic evidence of parenchymal infection is seen in
70% of children and 90% of adults 1. Cavitation is uncommon in primary TB, seen only in 10-30% of
cases 2. In most cases, the infection becomes localized and a caseating granuloma forms
(tuberculoma) which usually eventually calcifies and is then known as a Ghon lesion 1-2.

The more striking finding, especially in children, is that of ipsilateral hilar and contiguous mediastinal
(paratracheal) lymphadenopathy, usually right-sided 3. This pattern is seen in over 90% of cases of
childhood primary TB, but only 10-30% of adults 1. These nodes typically have low-density centers with
rim enhancement on CT 1-3. Occasionally these nodes may be large enough to compress adjacent
airways resulting in distal atelectasis 1.

Pleural effusions are more frequent in adults, seen in 30-40% of cases, whereas they are only present
in 5-10% of pediatric cases 1.

As the host mounts an appropriate immune response both the pulmonary and nodal disease resolve.
Calcification of nodes is seen in 35% of cases 2. When a calcified node and a Ghon lesion are present,
the combination is known as a Ranke complex.

Post-primary pulmonary tuberculosis

Post-primary pulmonary tuberculosis, also known as reactivation tuberculosis or secondary
tuberculosis occurs years later, frequently in the setting of a decreased immune status. In the
majority of cases, post-primary TB within the lungs develops in either 1-2:

1. posterior segments of the upper lobes

 2. superior segments of the lower lobes
Typical appearance of post-primary tuberculosis is that of patchy consolidation or poorly defined
linear and nodular opacities 1.

Post-primary infections are far more likely to cavitate than primary infections and are seen in 20-45%
of cases. In the vast majority of cases, they develop in the posterior segments of the upper lobes
(85%)1,5. The development of an air-fluid level implies communication with the airway, and thus the
possibility of contagion. Endobronchial spread along nearby airways is a relatively common finding,
resulting in relatively well-defined 2-4 mm nodules or branching lesions (tree-in-bud sign) on CT 1,3.

Hilar nodal enlargement is seen in only approximately a third of cases 1. Lobar consolidation,
tuberculoma formation, and miliary TB are also recognized patterns of post-primary TB but are less
common.

Tuberculomas account for only 5% of cases of post-primary TB and appear as a well defined rounded
mass typically located in the upper lobes. They are usually single (80%) and can measure up to 4 cm in
size. Small satellite lesions are seen in most cases 1. In 20-30% of cases, superimposed cavitation may
develop.

Miliary pulmonary tuberculosis

Miliary tuberculosis is uncommon but carries a poor prognosis. It represents hematogenous
dissemination of an uncontrolled tuberculous infection. It is seen both in primary and post-primary
tuberculosis. Although implants are seen throughout the body, the lungs are usually the easiest
location to image.

Miliary deposits appear as 1-3 mm diameter nodules, which are uniform in size and uniformly
distributed 1-2. If the treatment is successful, no residual abnormality remains.

References
1. Müller NL, Franquet T, Lee KS et-al. Imaging of pulmonary infections. Lippincott Williams &
Wilkins.2007. 

2. Collins J, Stern EJ. Chest radiology, the essentials. Lippincott Williams & Wilkins.2007.

3. Naidich DP, Srichai MB, Krinsky GA. Computed tomography and magnetic resonance of the
thorax. Lippincott Williams & Wilkins.2007.

4. Kazerooni EA, Gross BH. Cardiopulmonary imaging. Lippincott Williams & Wilkins.2004.

5. Leung AN. Pulmonary tuberculosis: the essentials. Radiology. 1999;210 (2): 307-22. 
Tuberculosis (TB) is caused by a bacterium called Mycobacterium tuberculosis. The bacteria usually
attack the lungs, but TB bacteria can attack any part of the body such as the kidney, spine, and brain.
Not everyone infected with TB bacteria becomes sick. As a result, two TB-related conditions exist:
latent TB infection (LTBI) and TB disease. If not treated properly, TB disease can be fatal.

How TB Spreads
TB bacteria are spread through the air from one person to another. The TB bacteria are put into the
air when a person with TB disease of the lungs or throat coughs, speaks, or sings. People nearby may
breathe in these bacteria and become infected.

TB is NOT spread by

 shaking someone’s hand

 sharing food or drink
 touching bed linens or toilet seats
 sharing toothbrushes
 kissing

When a person breathes in TB bacteria, the bacteria can settle in the lungs and begin to grow. From
there, they can move through the blood to other parts of the body, such as the kidney, spine, and
brain.

TB disease in the lungs or throat can be infectious. This means that the bacteria can be spread to
other people. TB in other parts of the body, such as the kidney or spine, is usually not infectious.

People with TB disease are most likely to spread it to people they spend time with every day. This
includes family members, friends, and coworkers or schoolmates.