L3 Tuberculosis

Objectives:
1. Describe tuberculosis
a. Causative agent, its mode of transmission and virulence factor
b. Risk factors
c. Types and pathogenesis
d. Diagnosis (clinical presentation, X-ray, lab diagnosis)
e. Complications
f. Treatment and preventive measures

Concept
1. A serious bacterial infection that is characterised by presence of chronic granulomatous
inflammation
2. The pathogenesis of tuberculosis depends on the host’s immune response (high risk of
tuberculosis in immunosuppressed individuals)
Aetiology
1. CA
a. Mycobacterium tuberculosis (99%)
i. Known as acid- & alcohol-fast bacilli
ii. Rod-shaped, obligate aerobic, intracellular pathogen
iii. Grows very slowly on culture media
iv. Has lipid-rich cell wall = mycolic acid
v. Virulence factors:
1. Presence of mannose-capped glycolipid on its cell wall that allows
the bacteria to bind macrophages
2. Able to survive and multiply inside the macrophages by avoiding
lysosomal killing
b. Mycobacterium bovis (causing oropharyngeal & intestinal TB)
2. MOT
a. Person-to-person via inhalation of infected aerosols

Risk Factors
1. HIV infection
2. Alcoholism
3. Patients in immunosuppressive therapy e.g. corticosteroids
4. Diabetic patients
5. History of recent surgery
6. Workers in healthcare facilities

Types & Pathogenesis

1. Primary TB
a. Occur in non-sensitised patients (getting infection for the first time)
b. Pathogenesis
i. Inhalation of M. tuberculosis (of droplets from infected person)
ii. Bacilli reach the lungs and get lodged in the upper part of lower lobe →
mannose-capped glycoprotein present on the bacilli binds to mannose
receptor present on the alveolar macrophages
iii. Recognised and engulfed by alveolar macrophages
iv. Bacilli able to survive inside the macrophages by avoiding lysosomal killing
and multiply within the macrophages (w/in 3 weeks of infection)
v. Activation of CMI in tuberculosis
 1. Ineffective mycobacterial eradication prior to initiation of
cell-mediated immunity further results in mycobacterial proliferation
with significant death of alveolar macrophages which further causes
tissue injury.
2. Surviving alveolar macrophages that are exposed to mycobacteria
then initiates delayed-type hypersensitivity reaction by presenting
the mycobacterial antigens to T cells resulting in its activation
forming CD4+ T cells which mediated by IL-12 secreted by the
alveolar macrophages themselves.
3. Activated CD4+ T cells then secretes IFN-𝜸 which results in
activation of macrophages that will release TNF-𝝰 to recruit
monocytes to the site of inflammation followed by its activation,
and also mediate in the production of nitric oxide, reactive oxygen
species as well as defensins release, thus increasing the
mycobactericidal activity (effective killing of mycobacteria).
4. Simultaneously, IFN-𝜸 secreted by CD4+ T cells initiates
granulomatous inflammation by differentiation of activated
macrophages to form epithelioid histiocytes surrounding the
central caseous necrosis forming granuloma along with fusion of
activated macrophages (Langhans giant cells) in attempt to restrict
the infection from further causing tissue damage.
5. Central caseous necrosis contains damaged tissues, dead
mycobacterium-ingested alveolar macrophages and dead
mycobacteria which liberates mycolic acid thus contributing to the
lipid-rich characteristic of caseous necrosis, giving it a cheese-like
appearance.
a. Macrophages response results in inflammation ⇒ numerous
granuloma (Gohn’s focus)
b. Over time, the centre of the lesion undergoes caseous
necrosis giving grossly cheese-like appearance to the
affected lung
vi. Dissemination of bacilli to other parts of the body via lymphatic and
bloodstream (patient is asymptomatic or showing mild flu-like illness)
1. Dissemination to the lymph nodes causing inflammation in the
lymph nodes (MIliary TB)
a. Gohn’s foci + lymphadenopathy ⇒ Gohn complex
2. Secondary TB
a. Occur in sensitised patients (in patients that has previous exposure to TB)
b. More commonly occurs decades after the primary infection
c. Pathogenesis
i. Re-entry of M. tuberculosis or reactivation of latent bacilli (reinfection)
ii. Lesions involves the apex of the upper lobe of one or both lungs
iii. Progression leads to erosion of the bronchial wall and leakage of the
contents into the airways (cavitation)
iv. Causing dissemination through airways and spread to other lobes, URT;
swallowing of infectious sputum leads to intestinal tuberculosis
Complications
1. Most often resembles an acute bacterial pneumonia
a. Pleural effusion → pleuritic chest pain
b. Lung collapse → atelectasis
 c. Cavitation (Secondary TB) → due to leakage of contents into the airways
d. Lower & middle lobe consolidation seen in chest x-ray (Primary TB)
e. Dissemination leads to:
i. Miliary TB → due to massive hematogenous dissemination
ii. TB meningitis
iii. TB lymphadenitis
iv. TB spine (Pott’s disease)
Diagnosis
1. Clinical presentation
a. Persistent chronic dry/productive cough of more than 2 weeks
b. Low grade fever, remittent (occurs in late afternoon then subsides at night)
c. Anorexia leading to weight loss
d. Hemoptysis (severe TB)
e. Pleuritic type chest pain
2. X-ray imaging
a. White consolidations
3. Lab diagnosis
a. Blood test
i. Elevated IFN-𝜸 → mediates in formation of caseating granuloma in
tuberculosis
b. Sputum sample stained in Ziehl Nielsen stain
i. Appears bright red
c. Mycobacterium culture
i. Highly sensitive, able to differentiate between species
ii. But takes very long time (4 - 12 weeks) as the bacteria grows very slowly
iii. White, buffy colonies on Lowenstein-Jensen Medium
d. PCR
i. Rapid detection
e. Mantoux test
i. As screening method to identify active infection or previous infections of TB
1. Intradermal injection of purified protein derivative (PPD)
2. Type IV hypersensitivity reaction seen in patients that has previous
TB infection
Treatment
1. 6 months treatment with antibiotics
2. Anti-TB drugs: (first line)
a. Isoniazid
b. Rifampicin
c. Pyrazinamide
d. Ethambutol
e. Streptokinase
3. First line drugs
Drugs Role PK MOA SE DI

Isoniazid (H) - Most - Taken orally → well - A prodrug → activated by bacterial Nausea; vomiting; - Antacid inhibit isoniazid
powerful/efficacious absorbed in the GIT → 20% catalase → inhibit the synthesis of hepatotoxicity; absorption
anti-TB drug penetration to CSF → mycolic acid peripheral - Isoniazid inhibit low therapeutic
- Rapidly makes metabolism is by acetylation - Bactericidal against actively growing neuropathy; index drugs metabolism → inhibit
patient - Active in acidic environment intracellular & extracellular M. rashes; acne biotransformation → less
non-infectious tuberculosis excretion in the urine → increase
- Penetrate well to - Non-effective to atypical mycobacteria in blood levels --. toxicity
caseous granuloma
Rifampicin (R) - Active against - Taken orally → well
dormant bacilli; and absorbed in the GIT → widely
intracellular distributed → penetrate
organisms cavities, caseous masses,
placenta, meninges
- Metabolites undergoes
enterohepatic circulation →
very little of it will be excreted
→ longer duration of action
Inhibits bacterial DNA-dependent RNA Body fluids - An enzyme inducer → increases
polymerase → inhibit bacterial become orange in drug biotransformation in the
DNA-dependent RNA synthesis → colour (harmless); liver → increased excretion in the
bactericidal effect (intracellular) fever; arthralgia; urine → decrease in drug efficacy
hepatotoxicity; and duration of action
rash; pruritus;
headache

Pyrazinamide (Z) - Active against Taken orally → well absorbed - Diffuse into granuloma of M, Drug-induced
intracellular; dormant in the GIT tuberculosis → conversion to pyrazinoic hepatitis; nausea
bacilli acid by bacterial pyrazinamidase → & vomiting;
- Highly effective in ● Inhibit fatty acid synthetase arthralgia,
first 2 months (FAS) I hyperuricemia.
- Can reduce duration ● Disrupts membrane potential Hepatotoxicity,
of treatment → interferes with energy urticaria, pruritus
production etc.
● Bind to ribosomal protein S1
(RpsA) → inhibiting translation
→ bactericidal effect

Ethambutol (E) - Active against Taken orally → well absorbed Inhibits arabinosyl transferase → inhibit Optic neuritis →
atypical mycobacteria in the GIT → widely arabinogalactan synthesis → prevention color blindness;
- Hasten the rate of distributed in all tissues production of bacterial cell wall complex peripheral
sputum conversion → increase in cell wall permeability → neuropathy;
- Prevent selectively bacteriostatic effect arthralgia;
development of hyperuricemia;
resistance vertical nystagmus

Streptomycin (S) - Not very much Given IV/IM Binds to 30S subunit of the bacterial Vertigo; vomiting;
significant as first-line ribosome → interfering its binding to ototoxicity;
drugs formyl-methionyl-tRNA → codon nephrotoxicity;
- Acts only on misleading → inhibition of protein neuromuscular
extracellular bacilli synthesis → bactericidal effect blockade
with poor penetration
into cells

4. Second line drugs

Drug Role PK MOA SE

Ethionamide - Acts both intracellular & Taken orally → well A prodrug → activated by ethA Nausea & vomiting; hepatotoxicity,
extracellular, atypical absorbed in GIT → widely enzyme in the bacteria → bind to peripheral neuropathy,
mycobacteria distributed → short NAD+ thus inhibiting mycolic acid encephalopathy
- Important in MDR-TB duration of action synthesis

Prevention
1. Isolation of infected patients
2. Contact tracing and screening
3. Early detection and treatment
4. Vaccination
a. BCG vaccine
i. Live attenuated vaccine - Bacillus Calmette Guerin (reduced virulence type
of M. bovis
ii. Given at birth