Tuberculosis

Question 1

What type of inflammation do you get in TB?

Answer 1

Tuberculosis is an example of granulomatous inflammation.

Question 2

What causes TB?

Answer 2

Mycobacterium tuberculosis, a small rod-shaped bacillus with a thick lipid-rich cell wall.

Question 3

Is mycobacterial slow growing or fast growing?

Answer 3

Mycobacteria are remarkably slow growing and are able to persist in a latent from within cells for many years, allowing reactivation of disease many years after infection was first acquired.

Question 4

How is TB spread?

Answer 4

TB is almost always spread by the respiratory route from a patient with “open” or “smear positive” active TB. Having said that, the intact respiratory mucosa is very resistant to invasion by microorganisms. Infection therefore begins in the terminal air spaces right at the periphery of the lungs, usually just beneath the pleural surface.

Question 5

What happens to bacilli ones they are inhaled?

Answer 5

Bacilli inhaled into the terminal airways are engulfed by alveolar macrophages.

Question 6

Alveolar macrophages can destroy mycobacteria T/F?

Answer 6

Alveolar macrophages are unable to destroy the mycobacteria because their thick cell wall resists attack.

Question 7

What happens once the TB microorganism is able to survive?

Answer 7

Survival of the organism allows it to multiply within macrophages, eventually leading to cell death and release of more microorganisms. Over a period of weeks, mycobacteria spread in macrophages via the blood to the apices of the lungs and multiple other organs such as the kidneys, adrenals, bones and meninges.

Question 8

Most patients with disseminated TB are asymptomatic T/F?

Answer 8

In the majority (95%) of infected individuals this dissemination remains entirely asymptomatic.

Question 9

What is the mechanism by which T cell mediated immunity is established against mycobacteria tuberculosis?

Answer 9

After a few weeks, T cell mediated immunity is established: 
	• Macrophages (acting as antigen presenting cells) activate mycobacteria-specific CD4+ T helper cells via MHC class II. 
	• The Th1 T helper cells produce interferon-g. This cytokine is a powerful activator of macrophages.

Question 10

How is a granuloma formed in TB?

Answer 10

Activated macrophages aggregate around mycobacteria to form granulomas. The granulomas wall off viable organisms in an anoxic and acidic environment which does not favour mycobacteria survival. In other words, the granulomas that form in TB infection are protective.

Question 11

What are the characteristics of a TB granuloma

Answer 11

The centre of the lesion becomes necrotic with an appearance like soft cheese (caseous necrosis), and most of the bacteria die. The lesion eventually becomes quiescent and sealed off by fibrous scar tissue which may calcify. A few bacilli may, however, survive in a dormant form and cause reactivation of TB months or years later.

Question 12

What is a granuloma?

Answer 12

Aggregate of activated (epitheloid) macrophage

Question 13

What is the ultimate result of granuloma formation in TB?

Answer 13

In over 95% of cases, development of specific cell-mediated immunity is protective and holds the organism in check.
The ultimate result is a calcified scar in the lung parenchyma and the hilar lymph node.
Together this is referred to as the Ghon complex

Question 14

What is active TB?

Answer 14

Active TB (where mycobacteria are growing and causing symptoms/signs of disease)

Question 15

What are the main circumstances where active TB may be seen?

Answer 15

• A small majority of people are unable to contain the initial infection due to an inadequate T cell immune response –> progress immediately to active TB.
• Reactivation of latent disease.
Often the underlying cause for reactivation is clear e.g. immunosuppression. However, in many cases, there is no obvious immunodeficiency and the underlying reason for reactivation is unclear.

Question 16

Who is at risk of active TB?

Answer 16

• Immunocompromised individuals, particularly HIV.
○ HIV infects CD4 T helper cells. As a consequence of HIV, the CD4 count is reduced and this impairs cell-mediated immunity. There may be reactivation of latent TB as cell-mediated immunity becomes impaired by HIV.
• Immigrants from countries with high rates of tuberculosis
• Elderly
• Alcoholics
Diabetes mellitus

Question 17

What kind of immune response is activated TB related to?

Answer 17

Active TB is related to an inappropriate T helper cell response:
• A strong Th1 response is associated with protective immunity resulting in granuloma formation which contains the infection
• If, however, the T helper cell response is more Th2 driven, an inappropriate repertoire of immune cells are recruited.
–> there is an intense but ineffective immune response to the organism which leads to extensive tissue destruction and survival of the organisms.

Question 18

How should TB be classified?

Answer 18

• In the past active TB has been classified as either “primary” (newly acquired infection) or “post-primary” (reactivation).
• Recent evidence suggests that this distinction is unreliable since many patients presumed to have reactivation in fact are shown by DNA studies to have a newly acquired infection.
–> A better classification for active TB is pulmonary and extrapulmonary.

Question 19

How does active pulmonary TB present?

Answer 19

Active pulmonary TB presents as a chronic pneumonia.
The most common symptoms:
• Feeling unwell for weeks or months
• Persistent cough
Constitutional symptoms e.g. fever, night sweats, loss of appetite and weight

If an enlarging focus erodes into an airway, the bacilli can enter the sputum - the patient has “open” tuberculosis.
If a major airway is involved, the necrotic material drains away and the focus transforms into a cavity containing enormous numbers of organisms in the cavity wall. Patients with cavitating TB are particularly infectious because their sputum contains large numbers of mycobacteria and they cough frequently.

Question 20

What is the definition of active TB disease?

Answer 20

infection with M. tuberculosis where mycobacteria are growing and causing symptoms and signs of disease

Question 21

What is the definition of latent infection?

Answer 21

Infection with M. tuberculosis where mycobacteria are alive but not currently causing active disease

Question 22

How is active TB diagnosed?

Answer 22

The diagnosis of active pulmonary TB is based on a combination of findings:
• Compatible history
• Radiological findings
○ E.g. CXR or CT showing infiltrates involving upper lobes +/- cavitation.
• Laboratory features (microscopy and culture):
○ 3 respiratory samples (preferably spontaneously produced, deep cough sputum samples, otherwise induced sputum or bronchoscopy and lavage; preferably 1 early morning sample).
○ Microscopic examination of samples spread on to a slide (a sputum smear) and stained with the Ziehl-Neelsen stain.
○ Culture remains the gold standard to confirm the diagnosis of M. tuberculosis (since other non-tuberculosis bacteria can be found in sputum and are acid fast) and determine sensitivities. The problem with culture is that the result takes 3-6 weeks due to the slow-growing nature of the organism. If clinical features are consistent with a diagnosis of tuberculosis, treatment is started without waiting for culture results.

Question 23

NAAT and TB?

Answer 23

Nucleic acid amplification test (NAAT) is a test to detect fragments of nuclei acid, allowing rapid and specific diagnosis of M. tuberculosis directly from different clinical samples. It may be indicated for a variety of reasons including: if there is a clinical suspicion of TB disease, the person has HIV infection or rapid information about mycobacterial species would alter the patient’s care.

Question 24

What is extra-pulmonary TB?

Answer 24

About 15% of cases of active TB involve organs other than the lungs, most commonly in children and immunocompromised adults.
During the initial infection, haematogenous dissemination of bacilli to a number of organs can occur. These localised infections usually become walled off in small granulomas where mycobacteria remain dormant. If they reactivate at a later time –> extrapulmonary TB.

Question 25

What are the most common sites of extrapulmonary TB?

Answer 25

The most common sites of involvement are lymph nodes (mainly cervical and supraclavicular) and kidneys. Patients with severely impaired immunity may develop rapidly progressive disease with wide dissemination resulting in numerous small foci of infection developing in many organs - milliary TB.

Question 26

Once a diagnosis of TB has been confirmed, what are the next steps?

Answer 26

Once the diagnosis is confirmed there are important steps to take:
• Antituberculous therapy should be commenced - often quadruple therapy (rifampicin, isoniazid, pyrazinamide, ethambutol - RIPE). Patient compliance should be monitored.
• TB is notifiable disease, and so the diagnosis must be notified.
• Contact tracing should be undertaken for those with active pulmonary disease.