Tuberculosis (TB) - Overview & Pathophysiology

The Organism

Mycobacterium tuberculosis (MTB) is an obligate aerobic, non-spore-forming, non-motile bacillus. Its defining feature is an unusually thick, waxy cell wall rich in mycolic acids, which:

Makes it acid-fast (retains carbol-fuchsin dye in the Ziehl-Neelsen stain)
Resists phagolysosomal killing
Allows intracellular survival inside macrophages
Enables airborne transmission via tiny droplet nuclei (1-5 µm) that reach the alveoli

The organism is classified into distinct phylogenetic lineages. "Modern" lineages 2-4 drive the global epidemic; lineage 2 strains are particularly associated with rapid drug resistance development and greater transmissibility. - Goldman-Cecil Medicine, p. 3249

Epidemiology

The WHO estimates 1.7 billion people (a quarter of the world's population) carry latent MTB infection. In 2021, approximately 1.3 million people died of TB worldwide, making it historically the leading infectious cause of death from a single pathogen (surpassed only by SARS-CoV-2 during the COVID-19 pandemic). HIV coinfection profoundly amplifies risk: HIV-positive individuals are 25-30 times more likely to develop active TB from latent infection. - Robbins Basic Pathology, p. 474; Goldman-Cecil Medicine, p. 3249

Step 1 - Infection Before Cell-Mediated Immunity (First ~3 Weeks)

When droplet nuclei are inhaled, bacilli deposit in the distal air spaces of the lower upper lobe or upper lower lobe (zones of greatest airflow). They are engulfed by alveolar macrophages via mannose receptors and complement receptor 3 (CR3). MTB then employs a critical virulence strategy:

Phagosome maturation arrest - blocks fusion with lysosomes
Inhibits acidification of the phagosome
Blocks production of reactive nitrogen and oxygen species

The result is unchecked intracellular bacterial replication, leading to bacteremia with seeding of multiple sites (lungs, lymph nodes, kidneys, meninges, bone) before immunity develops. - Robbins Basic Pathology, p. 475

Step 2 - Cell-Mediated Immunity (After ~3 Weeks)

Once MTB antigens reach draining lymph nodes, dendritic cells and macrophages present them to CD4+ T cells. Under the influence of macrophage-secreted IL-12, naive T cells differentiate into Th1 cells, which then secrete IFN-γ. This is the pivotal cytokine in TB immunity.

IFN-γ activates macrophages to:

Produce TNF-α - recruits monocytes that form the granuloma
Upregulate iNOS (inducible nitric oxide synthase) - generates nitric oxide (NO) and reactive nitrogen intermediates that kill mycobacteria
Produce defensins (antimicrobial peptides) toxic to MTB
Achieve phagolysosome maturation to actually digest the bacillus

The IFN-γ / TNF / CD4 T-cell axis is so essential that defects in IL-12 signaling, IFN-γ, TNF, or NO production all result in poorly formed granulomas and disease progression. This explains why anti-TNF-α therapies (e.g. infliximab for RA/IBD) carry a black-box warning for TB reactivation. - Robbins Basic Pathology, p. 475-476

Sequence of events in primary pulmonary tuberculosis - cellular immune response

Fig. 11.34 from Robbins Basic Pathology - natural history of primary pulmonary TB, showing events before (A) and after (B) cell-mediated immunity develops.

The Granuloma - Hallmark Lesion

The tuberculous granuloma (tubercle) forms when IFN-γ drives macrophages to differentiate into epithelioid histiocytes, which aggregate around the bacilli. Some fuse into Langhans-type multinucleate giant cells (nuclei arranged at periphery). Surrounding this core are sensitized T lymphocytes.

Centrally, a process unique to TB occurs: caseous necrosis - an amorphous, cheese-like coagulative necrosis with complete effacement of tissue architecture. This results from:

Intense delayed-type hypersensitivity
Local ischemia
Toxic bacterial products

The caseum is largely devoid of living cells but can contain viable organisms. In immunocompetent hosts, the granuloma walls off and controls the infection. In immunocompromised hosts (HIV, malnutrition, anti-TNF therapy), granuloma formation fails and instead sheets of macrophages with unchecked bacillary growth are seen. - Robbins Basic Pathology, p. 475-476

Primary TB

Primary TB occurs in a previously unexposed, unsensitized individual. About 5% of newly infected individuals develop significant disease.

Ghon focus: A 1.0-1.5 cm gray-white area of consolidation, usually subpleural in the lower upper lobe or upper lower lobe, often with central caseous necrosis.

Ghon complex: Ghon focus + lymphangitis + regional hilar/mediastinal lymph node caseation. This triad is the hallmark of primary infection.

In ~95% of immunocompetent people, cell-mediated immunity controls infection and the Ghon complex undergoes progressive fibrosis and calcification (visible on X-ray as the Ranke complex). Despite early hematogenous seeding, no further lesions develop. - Robbins Basic Pathology, p. 474-476

Latent TB Infection (LTBI)

In the remaining ~90% who never develop active disease, MTB enters a state of dormancy. The bacteria survive within the granuloma, metabolically suppressed. Organisms may persist in:

Macrophages
Lymph node lymphatic endothelial cells (LECs) - recently identified reservoir

Lifetime risk of reactivation from LTBI: 5-10%. - Tietz Laboratory Medicine; Murray & Nadel's

Secondary (Reactivation) TB

Secondary TB arises in a previously sensitized host, either from:

Reactivation of dormant primary lesions (typically decades later)
Reinfection with a large inoculum

Characteristic location: apex of one or both upper lobes (highest oxygen tension favors aerobic MTB growth). Because hypersensitivity pre-exists, the immune response is rapid and tends to wall off the focus, so regional lymph node involvement is far less prominent than in primary TB.

Without adequate control, the caseous center liquefies (due to proteolytic enzymes), ruptures into a bronchus, is expectorated, and leaves behind a cavity. This is the basis of:

Cavitary TB on CXR
Infectious aerosol transmission (open TB)
Hemoptysis (erosion into pulmonary vessels - Rasmussen aneurysm)

Secondary TB can also disseminate hematogenously to produce miliary TB (millet seed-sized granulomas throughout the body) when immune control completely fails. - Robbins Basic Pathology, p. 476-478

Summary Flowchart

Inhalation of droplet nuclei (1-5 µm)
        ↓
Alveolar macrophage engulfs MTB
        ↓
MTB blocks phagolysosome fusion → intracellular replication
        ↓
Hematogenous/lymphatic seeding (bacteremic phase)
        ↓ [~3 weeks]
IL-12 → CD4+ Th1 cells → IFN-γ
        ↓
Macrophage activation (iNOS, TNF, defensins)
        ↓
Granuloma formation with caseous necrosis
        ↓
    ┌──────────────────────────────┐
    │                              │
~95% Immunocompetent          ~5% Immunocompromised
Ghon complex → fibrosis/        Progressive primary TB
calcification (Ranke complex)   (no granulomas, sheets of
Latent TB infection             bacilli-laden macrophages)
    │
 Reactivation risk 5-10% lifetime
    ↓
Secondary TB: apical cavitary disease

Key Risk Factors for Progression to Active TB

Risk Factor	Mechanism
HIV (CD4 <200)	Depletes Th1 response
Anti-TNF therapy	Blocks granuloma maintenance
Diabetes mellitus	Impaired macrophage function
Malnutrition	Deficient cell-mediated immunity
Silicosis	Damages alveolar macrophages
End-stage renal disease	T-cell dysfunction
Age extremes	Immature/waning immunity

Goldman-Cecil Medicine, Table 299-1, p. 3250

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