Lower respiratory Infections
Tuberculosis
Tuberculosis: Overview
• TB is characterized as a necrotising granulomatous inflammation of infected
organs, most commonly the lungs
• The primary agent of TB is Mycobacterium tuberculosis
• Dissemination occurs via inhalation of infected droplets from people with active
pulmonary disease
• Exposure can lead to either primary active disease (5%) or asymptomatic latent
infection (95%)
• Latent disease is capable of reactivating to symptomatic disease if the immune system is
compromised (~5%)
• In 2018, estimates were 1.7 billion people infected worldwide with ~1.5 million
deaths
TB: Aetiology
• M. tuberculosis is a large non-motile, rod-shaped bacterium
• It is an obligate aerobe
• MTB complexes are always found in the well-aerated upper lobes of the lungs
• It is a facultative intracellular parasite, usually of macrophages
• It has a slow generation time - 15-20 hours
• A family of non-tuberculosis bacteria (NTM; 170 species) exists, some of which
can also cause pulmonary disease eg. M. avium complex (MAC)
• Many non-pathogenic mycobacteria are normal flora of humans
• All mycobacteria are stained for microscopy using the Ziehl-Neelson or acid fast
stain due to their unusual cell wall components
TB: Symptoms
General symptoms:
• Unexplained weight loss
• Loss of appetite
• Night sweats
• Fever
• Fatigue
If TB disease is in the lungs (pulmonary), symptoms may include:
• Coughing for longer than 3 weeks
• Haemoptysis
• Chest pain
If TB disease is in other parts of the body (extrapulmonary), symptoms will depend on the area affected
TB: Pathogenesis
• Infection begins with exposure to respiratory droplets containing M. tuberculosis
• A dose of 1-10 bacilli are dispersed, making the risk of transmission likely
• In the lung, the bacilli are phagocytised by alveolar macrophage cells, which then invade
the underlying epithelium
• Once inside the phagocyte, Mtb modulates the behavior of its phagosome by
preventing its fusion with acidic, hydrolytically-active lysosomes
• Monocytes from nearby blood vessels form the beginning of a granuloma, as the
immune system attempts to control disease
• this is the hallmark of tuberculosis
https://doi.org/10.1016/j.tim.2018.02.012
IMMUNE CHECK POINTS
https://doi.org/10.1016/j.tube.2018.09.007
TB and comorbidities
• Among HIV +ve individuals, TB is one of the most frequent opportunistic
infections
• Risk of developing TB is up to 26x higher in HIV+ve patients
• Due to weakened immune system
• TB may also exacerbate HIV-1 disease and AIDS progression
• Active TB is associated with higher HIV-1 viral loads in the blood
• T2D increases risk by ~7-fold
• Patients have a faster TB progression and respond poorly to treatment
• Other risks: IVDU, organ transplants
TB: Diagnostics
• TB disease is diagnosed by medical history, physical
examination, chest x-ray, and laboratory tests
• The TB skin test - Mantoux tuberculin skin test (TST) - give a
false-positive result in people who have received BCG
• IGRA’s – measure IFN-γ release in response to antigen
stimulation
• NAATS – molecular assays
TB: Treatment
• Should be initiated as early as possible – delays associated with poor clinical
outcomes
• Group 1 – first line oral antibiotics (for drug susceptible TB)
• INH; RIF; ETH; PZA
• Group 2 – second line injectables
• Amikacin; kanamycin; capreomycin; +streptomycin (1st line but injectable)
• Group 3 – Fluoroquinalones (inhibit DNA synthesis)
• Group 4 – second line bacteriostatics
• Ethionamide/prothionamide; para-aminosalicylic acid; cycloserine/terizidone
• Group 5: new or re-purposed drugs
https://www.sciencedirect.com/science/article/pii/S0753332217336557
Treating drug resistant TB
• Drug-resistant TB organisms are resistant to at least one first-line anti-TB drug
• Multidrug-resistant TB (MDR TB) is resistant to more than one anti-TB drug and at
least isoniazid (INH) and rifampin (RIF)
• Extensively drug-resistant TB (XDR TB) is resistant to isoniazid and rifampin, plus
any fluoroquinolone and at least one of three injectable second-line drugs (i.e.,
amikacin, kanamycin, or capreomycin
• Drug resistance is mediated by chromosomal mutations and rearrangements
