Infiltration of nonactivated macrophages → escape of humoral immune response
Multi-drug resistance: mutation in KatG (catalase-peroxidase) → INH conversion to its active metabolite → INH resistance
Pathophysiology
Primary tuberculosis
Ghon focus: a granuloma typically located in the middle/lower lung lobes.
Ghon complex: formed by the Ghon focus, regional lymph node, and the linking lymphatic vessels
The organisms can remain dormant in a walled-off Ghon complex for many years before reactivating.
Alternatively, the lesion may heal, forming a benign, calcified Ranke complex that is not associated with reactivation tuberculosis.
Secondary tuberculosis
In < 10% of individuals with primary TB, the host immune response fails to control the infection, leading to active primary TB and progressive disease.
In > 90% of individuals, the host immune response can control the infection, resulting in latent TB infection. Weakening of host immune response can allow reactivation of disease (or, less commonly, reinfection) and further disease progression.
Clinical features
Diagnostics
Active TB infection
Acid-fast bacilli smear microscopy
Description: Ziehl Neelsen stain or auramine rhodamine stain are used.
Advantages:
Rapid detection
Inexpensive
Disadvantages:
Low sensitivity
Cannot differentiate M. tuberculosis from other nontuberculous mycobacteria
Both viable and nonviable mycobacteria will stain
Nucleic acid amplification test
Description: For initial testing (along with AFB smear microscopy and culture) if clinical suspicion is high. Used for confirmation of AFB positive smears.
Advantages:
High specificity and sensitivity (lower sensitivity in individuals with a negative AFB smear)
Rapid diagnosis
Rapid detection of drug-resistant strains
Low cross-reactivity with nontuberculous mycobacteria
Disadvantages:
Requires laboratory equipment and trained staff, which may make use in resource-limited settings more difficult
Both viable and nonviable mycobacteria are detectable
Culture
Latent TB infection
Tuberculin skin test (purified protein derivative test, Mantoux test)
Mechanism
Tests cell-mediated immunity against M. tuberculosis via delayed hypersensitivity reaction (type IV HSR) mounted by T cells
Does not differentiate between active and latent TB
False positives resulting from either of the following:
Tests cell-mediated immunity against M. tuberculosis-specific antigens by measuring the amount of IFN-γ released by T cells using ELISA
Preferred test in individuals with prior BCG vaccination
Uses antigens that are found only in Mycobacterium tuberculosis, but not in BCG
Treatment
Rifamycins
Mechanism of action: inhibits bacterial DNA-dependent RNA-polymerase → prevention of transcription (mRNA synthesis) → inhibition of bacterial protein synthesis → cell death (bactericidal effect)
Isoniazid (INH)
Mechanism of action
Isoniazid is a prodrug and needs to be converted into its active metabolite by bacterial catalase-peroxidase (encoded by KatG).
Prevents cell wall synthesis by inhibiting the synthesis of mycolic acid
Pyrazinamide
Mechanism of action
Not completely understood
Prodrug: converted into active form pyrazinoic acid
Most effective at acidic pH (e.g., in acidic phagolysosomes)
Bactericidal effect
Ethambutol
Mechanism of action: inhibits arabinosyltransferase → ↓ carbohydrate polymerization → prevention of mycobacterial cell wall synthesis (bacteriostatic effect)
Side effects of antituberculosis agents
Isoniazid
Asymptomatic elevation of transaminases
In 10%-20% of patients, INH causes acute, mild hepatic dysfunction
In rare instances (<1%), INH induces a frank hepatitis that causes a syndrome similar to viral hepatitis (eg, fever, anorexia, nausea, jaundice)
Cytochrome P450 inhibition: leading to interactions with numerous drugs, including antiretroviral agents, cardiovascular agents, and antibiotics
Isoniazid is structurally similar to pyridoxine (vitamin B6), a cofactor for enzymes involved in synthesis of certain neurotransmitters. Because of this similarity, isoniazid acts as a competitive inhibitor of pyridoxine and can cause dose-related peripheral neuropathy (eg, numbness and tingling in the hands and feet).
CNS toxicity: precipitation of benzodiazepine-refractory seizures with high doses of isoniazid, psychosis, ataxia
Others: anion gap metabolic acidosis, pellagra, optic neuritis
Rifampin
Cytochrome P450 induction: leading to important interactions with ART in patients with HIV (therefore, rifabutin is preferred)
