What is tuberculosis

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I now have comprehensive, authoritative content from Robbins Pathology (both Basic and Pathologic Basis of Disease) and Harrison's. Let me compile a thorough answer.

Tuberculosis (TB)

Definition

Tuberculosis is a communicable chronic granulomatous infectious disease caused by Mycobacterium tuberculosis. It usually affects the lungs but can involve virtually any organ or tissue. It is the leading infectious cause of death worldwide, responsible for approximately 1.3 million deaths and 10.6 million new cases in 2022 - making it second only to COVID-19 among single infectious killers of adults globally.

Robbins, Cotran & Kumar Pathologic Basis of Disease, p. 350

Causative Organism

Mycobacterium tuberculosis is a slow-growing, aerobic, acid-fast bacillus. It belongs to the M. tuberculosis complex, which also includes M. africanum, M. bovis, and M. microti. M. bovis can cause oropharyngeal/intestinal TB via contaminated unpasteurized milk, though this is rare in countries with pasteurization.

Transmission

TB spreads primarily via airborne droplet nuclei - tiny particles expelled when an infected person coughs, sneezes, or speaks. Key points:

Only people with active (not latent) TB are contagious
Infection does NOT equal disease - most newly infected individuals develop an asymptomatic, self-limited pulmonary focus
Viable organisms can remain dormant in the body for decades

Epidemiology & Risk Factors

TB flourishes in settings of poverty, crowding, and chronic debilitating illness. High-risk groups include:

People living with HIV (890,000 of 10.6 million cases in 2022)
Immigrants from high-burden countries
Residents of crowded settings (prisons, shelters, long-term care)
People with: diabetes, Hodgkin lymphoma, silicosis, chronic renal failure, malnutrition, alcohol use disorder, and immunosuppression
Approximately 13 million people in the United States have latent TB

Pathogenesis (How TB Causes Disease)

After inhaled bacteria reach the alveoli, infection proceeds through these steps:

Entry into macrophages - M. tuberculosis is phagocytosed by alveolar macrophages via mannose-binding lectin and complement receptor 3 (CR3). The bacteria then spread to additional macrophages and dendritic cells.
Survival inside macrophages - The bacterium blocks phagolysosome fusion by recruiting the host protein coronin to the phagosome membrane, activating calcineurin and preventing lysosomal killing. The bacteria replicate unchecked within the phagosome.
Early dissemination - Within the first 3 weeks, bacteria proliferate in alveolar macrophages and air spaces, causing bacteremia and seeding multiple sites. Most people are asymptomatic or have a mild flu-like illness at this stage.
T cell-mediated immunity (Th1 response) - CD4+ T cells differentiate into Th1 cells and produce IFN-γ, which activates macrophages to kill the bacteria. This response controls infection but also causes tissue damage (caseating granulomas, cavitation).
Granuloma formation - Activated macrophages transform into epithelioid cells and multinucleated giant cells, forming the classic caseating granuloma (tubercle). Central necrosis takes on a "cheese-like" (caseous) appearance. If immune defenses are adequate, granulomas wall off the infection.

Robbins, Cotran & Kumar Pathologic Basis of Disease, pp. 350-352

Latent vs. Active TB

Feature	Latent TB	Active TB
Symptoms	None	Present
Contagious	No	Yes
Chest X-ray	Usually normal	Often abnormal
Sputum culture	Negative	Positive
Risk of progression	~5-10% lifetime	Ongoing disease

Types of TB Disease

Primary TB

The first infection in a previously unexposed person. Usually asymptomatic in healthy individuals. The only evidence may be a tiny fibrocalcific pulmonary nodule called a Ghon focus. In children or immunocompromised individuals, it can progress to severe disease.

Secondary (Reactivation) TB

Occurs when latent infection is reactivated due to lowered immunity. This is the most common form in adults. It typically involves the apices of the upper lobes (high oxygen tension favors bacterial growth). It can lead to:

Cavitary lung disease
Hemoptysis
Spread to other organs (miliary TB)

Extrapulmonary TB

Can involve lymph nodes, pleura, meninges (TB meningitis), spine (Pott's disease), kidneys, adrenals, peritoneum, pericardium, and joints. More common in young children, elderly, HIV-positive, and immunocompromised individuals.

Symptoms

Constitutional (systemic):

Fever (often low-grade, afternoon)
Night sweats
Fatigue and weakness
Weight loss and anorexia ("consumption" - the historical name)

Pulmonary:

Productive cough (lasting >3 weeks - classic hallmark)
Hemoptysis (coughing up blood)
Chest pain
Dyspnea in advanced disease

Diagnosis

Testing for infection (latent or active)

Tuberculin Skin Test (TST/Mantoux/PPD) - Intradermal injection of purified protein derivative; induration ≥5-15 mm (threshold varies by risk group) at 48-72 hours is positive
Interferon-Gamma Release Assays (IGRAs) - Blood test (e.g., QuantiFERON-TB Gold); T cells are stimulated with TB antigens and IFN-γ production is measured. More specific than TST; not affected by BCG vaccination

Both tests detect immune sensitization but cannot differentiate latent from active disease.

Diagnosing active TB

Chest X-ray - Upper lobe infiltrates, cavities, hilar adenopathy
Sputum smear microscopy - Acid-fast bacilli (AFB) staining (rapid but not sensitive)
Sputum culture - Gold standard; takes 2-6 weeks on solid media; faster with liquid broth systems (MGIT)
Nucleic Acid Amplification Tests (NAATs) such as Xpert MTB/RIF - Rapid diagnosis AND detects rifampin resistance simultaneously

Treatment

TB requires combination antibiotic therapy to prevent drug resistance and relapse.

Standard 6-month regimen (drug-susceptible TB)

Intensive phase (2 months): RIPE = Rifampin (R) + Isoniazid (I) + Pyrazinamide (P) + Ethambutol (E)
Continuation phase (4 months): Rifampin + Isoniazid

Drug-Resistant TB

MDR-TB = Resistant to both isoniazid and rifampin (~4% of new cases, 18% of previously treated cases globally in 2021). Requires second-line drugs (fluoroquinolones, bedaquiline, linezolid, etc.) for 18-24 months.
XDR-TB = MDR-TB plus resistance to fluoroquinolones and at least one injectable second-line drug. Extremely difficult to treat; ~8% of MDR-TB cases are XDR.

DOTS Strategy

The WHO's Directly Observed Therapy, Short-course (DOTS) strategy is the international framework for TB control, involving directly observed drug administration to ensure treatment completion.

Harrison's Principles of Internal Medicine 22E, pp. 1044-1050
Robbins & Kumar Basic Pathology, pp. 1157-1230

Prevention

BCG (Bacille Calmette-Guerin) vaccine - Live attenuated M. bovis; given at birth in high-burden countries. Protects against severe pediatric TB (meningitis, miliary TB) but offers variable protection against pulmonary TB in adults.
Treatment of latent TB infection (LTBI) - Isoniazid for 6-9 months, or shorter rifamycin-based regimens (3HP: 3 months of weekly isoniazid + rifapentine)
Infection control measures: ventilation, N95 masks, negative-pressure isolation rooms
Addressing social determinants: poverty reduction, improved housing

Global Burden (2025 Context)

TB remains seriously off-track from the WHO's End TB Strategy goal of a 90% reduction in incidence by 2035. The COVID-19 pandemic disrupted TB services worldwide and set back progress. Drug resistance continues to grow, and HIV co-infection remains a major driver in sub-Saharan Africa. As of 2022, approximately one-quarter of the world's population carries latent M. tuberculosis infection.

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