Tuberculosis

Mycobacterium tuberculosis is a bacillus that is acid-fast positive (Ziehl-Neelsen stain) and most commonly affects the lungs as it is transmitted through respiratory droplets.

We can divide it based on 2 patterns of disease of TB:

1. Primary TB - an initial infection, often in children. It causes granulomatous infection of the middle and lower lobes (subpleural granulomas) accompanied by ipsilateral hilar lymph node infection. This is known as a Ghon complex. These granulomas often resolve and their is no further spread.

2. Secondary TB - mostly seen in adults as reactivation of the previous infection, especially when immunocompromised. The granulomatous inflammation has much wider spread and commonly affects the upper lobes. It is also common in malnourished patients and HIV patients. Immunocompromised patients may also have miliary TB (disseminated TB).

Mycobacterium tuberculosis enters the lungs and alveolar macrophages attempt to phagocytise them. However, MTB inhibits lysosomal fusion → creating a localised infection as it resides and multiplies within the macrophages.

These infected macrophages attract T-cells, B-cells, neutrophils which all surround these macrophages. Th1 cells then release IFN-y (interferon gamma) which stimulates these macrophages. This causes a morphological change of macrophages to form an epitheloid cell. MTB also induces dysregulated lipid metabolism → lipid accumulation → foamy macrophages which provides a suitable environment for MTB, allowing it to survive. The epitheloid cells fuse to form a multinucleate giant cell. A fibrous cuff surrounds the accumulation of cells leading to a highly vascularised cellular granuloma. The granuloma prevents spread of MTB and these patients are not infectious (latent TB). This granulomatous begins to necrose as cell lysis occurs, and a central necrotic caseum forms. This caseum and granuloma expands and eventually meets an airway, releasing the MTB reservoirs and allowing it to spread through aerosol inhalation once again.

It can be considered a type 4 hypersensitivity reaction.

Active TB requires inadequate containment by the immune system. It may occur as reactivation of latent TB or progression from primary infection.

Let’s discuss pulmonary TB and extrapulmonary TB…

PULMONARY TB

This is the most common type of TB.

😷 Presentations

🔍 Investigations

1. 🥇 Chest X-ray - is first-line. It is almost always abnormal in patients with normal immune systems. Typically presents with fibronodular opacities in upper lobes with/without cavitation. Atypically it presents with opacities in middle/lower lobes, hilar or paratracheal lymphadenopathy. Ghon complex can also be seen.

2. Sputum acid-fast bacilli smear - 3 specimens should be collected, 8 hours apart. Early morning specimen is best to detect MTB which stains pink on the stain. Sensitivity of 50-80% (decreases in HIV to 20-30%).
3. 🥇 Sputum culture - gold standard. More sensitive than a sputum smear and NAAT. Also can be used to assess drug sensitivity. Only issue is it takes very long (1-3 weeks with liquid media, solid media takes even longer).
4. NAAT - provides rapid diagnosis. More sensitive than smear but less than culture.
5. FBC - 10% of patients have leucocytosis and anaemia (microcytic).

👀 Screening

Screening is done for latent TB. We can use 2 tests mainly:

1. Mantoux test - involves intradermal injection of purified protein derivative (PPD) 0.1ml of 1:1000. The result is read 2-3 days later. It causes an induration in the skin and depending on the diameter of this induration, we can interpret it in certain ways:

Diameter of induration	Result	Interpretation
<6mm	Negative (no hypersensitivity to tuberculin protein).	Patient may be given BCG if not vaccinated.
6-15mm	Positive - hypersensitive to tuberculin protein.	No BCG to be given. May be due to previous TB infection or BCG vaccine.
>15mm	Strongly positive	Suggests TB infection

2. IGRA test - indicated if Mantoux is positive or if it is equivocal (ambiguous) or if it may be falsely negative. It measures the amount of interferon gamma released by T-cells in response to TB antigen. However, it has a high false negative rate of 20-25% and cannot distinguish between latent and active infection.

There may be false negatives due to:

🧰 Management

Management differs between active and latent TB:

Active TB

Antibiotics are given for very long periods (6 months or more)

1. 🥇 Initial phase

For the first 2 months we use 4 drugs - RIPE.

1. Rifampicin
2. Isoniazid
3. Pyrazinamide
4. Ethambutol

2. 🥇 Continuation phase

This continues for the next 4 months and only involves 2 of the 4 drugs initially started:

1. Rifampicin
2. Isoniazid

⚠️

For meningeal, pericardial and spinal tuberculosis treatment continues for at least 12 months with steroids

Latent TB

Directly observed therapy of a 3 times a week dosing regimen may be indicated in homeless people with active TB, patients likely to have poor compliance, prisoners with TB (latent or active).

🚨 Complications

Let’s talk about the drug complications in the treatment of TB predominantly:

Rifampicin

Works by inhibiting RNA polymerase which prevents DNA transcription into mRNA for translation.

Adverse effects include:

1. Potent CYP inducer
2. Hepatitis
3. Orange secretions - tears, urine, saliva, sweat may be reddish-brown.
4. Flu-like symptoms

Ethambutol

Inhibits arabinosyl transferase which prevents the arabinogalactan layer binding to the mycolic acid layer.

EXTRAPULMONARY TB