Tuberculosis (TB) — Harrison's Principles of Internal Medicine, 22nd Edition (2025)

Overview

Etiologic Agent

• M. tuberculosis (sensu stricto) - by far the most important human pathogen
• M. africanum - closely related, cases in West, Central, and East Africa
• M. bovis - bovine tubercle bacillus; resistant to pyrazinamide; ~140,000 human cases/year (2020), mainly in Africa; transmitted via unpasteurized milk
• M. caprae - related to M. bovis
• Other rare agents: M. pinnipedii, M. mungi, M. microti (the "vole" bacillus - less virulent), M. canetti

• Rod-shaped, non-spore-forming, thin aerobic bacterium: 0.5 x 3 μm
• Neutral on Gram staining; classified as acid-fast bacilli (AFB) - once stained, cannot be decolorized by acid alcohol
• Acid fastness due to high content of mycolic acids, long-chain cross-linked fatty acids, and other cell-wall lipids
• Other acid-fast organisms: Nocardia, Rhodococcus, Legionella micdadei, Isospora, Cryptosporidium
• Cell wall structure: lipids (mycolic acids) linked to arabinog alactan and peptidoglycan - results in very low permeability, reducing effectiveness of most antibiotics
• Genome: 4.4 million base pairs, 4043 genes, high G+C content (65.6%)

Fig. 183-1: AFB smear showing M. tuberculosis bacilli (CDC)

Epidemiology

• 10.8 million estimated new TB cases worldwide in 2023 (rate: 134/100,000)
• 8 countries account for two-thirds of all cases: India (26%), Indonesia (10%), China (6.8%), Philippines (6.8%), Pakistan (6.3%), Nigeria (4.6%), Bangladesh (3.5%), DRC (3.1%)
• 55% males, 33% females, 12% children
• 1.25 million deaths from TB in 2023, including 160,000 among HIV co-infected persons; 98% in low- and middle-income countries
• ~97% of cases from low- and middle-income countries

• HIV-infected individuals (highest risk)
• Close contacts of active TB cases
• Immigrants from high-prevalence countries
• Healthcare workers
• Incarcerated persons
• Persons with silicosis, DM, malnutrition, renal failure, TNF-α inhibitor therapy

Pathogenesis and Immunity

Transmission

Natural History After Infection

1. Droplet nuclei reach alveoli and are ingested by alveolar macrophages
2. If not eliminated, bacilli multiply within macrophages
3. Bacilli spread via lymphatics to regional lymph nodes (primary complex / Ghon complex)
4. Early hematogenous spread seeds the lungs and other organs (kidneys, bones, brain)
5. Cell-mediated immunity develops within 2-10 weeks, usually halting multiplication
6. ~90-95% of infected individuals develop latent TB infection (LTBI) without disease
7. In ~5-10%, primary TB or subsequent reactivation TB develops

In the lung cavity:

• Bacilli spill into airways from caseous foci, multiply within the cavity, and discharge into the environment through coughing and talking
• In young children with poor natural immunity, hematogenous dissemination may result in fatal miliary TB or tuberculous meningitis

Role of Macrophages and Monocytes

• Alveolar macrophages phagocytose bacilli; alternatively activated macrophages are more susceptible to early growth
• Bactericidal activity mediated by reactive oxygen intermediates (ROI) and nitric oxide
• Cytokines secreted: TNF-α, IL-1 regulate release of reactive intermediates; TNF-α is key - too much leads to immunopathology, too little leads to inadequate containment
• Macrophages can undergo apoptosis as a defensive mechanism
• Neutrophils also involved, though timing and effectiveness remain uncertain

Role of T Lymphocytes

• CD4+ T lymphocytes are crucial - defects in CD4+ cells (e.g., HIV infection) explain inability to contain mycobacterial proliferation
• TH1 cells produce IFN-γ (activates macrophages) and IL-2
• TH2 cells produce IL-4, IL-5, IL-10, IL-13 and promote humoral immunity
• CD8+ T cells - cytotoxic responses, lysis of infected cells
• IFN-γ induces reactive oxygen/nitrogen intermediates and regulates bactericidal genes
• Granuloma formation: hallmark of host response, contains but may not eliminate infection

Clinical Features

Pulmonary TB (most common - ~2/3 of cases)

• Productive cough (often weeks to months)
• Hemoptysis
• Fever, night sweats
• Weight loss, anorexia, fatigue ("consumption")
• Chest pain (with pleuritis)
• Dyspnea (extensive disease)

• Primary TB: hilar/paratracheal lymphadenopathy, lower/mid-zone consolidation, pleural effusion
• Reactivation TB (most common form): upper lobe infiltrates, cavitation (pathognomonic), fibrosis, calcified nodules (Ghon complex)
• Miliary TB: diffuse bilateral 1-2 mm nodules ("millet seeds")

Extrapulmonary TB (up to 1/3 of cases)

Diagnosis

Latent TB Infection (LTBI) Diagnosis

1. Tuberculin Skin Test (TST / Mantoux):
   • 5 TU PPD injected intradermally; read at 48-72 h
   • Positive: ≥5 mm (HIV+, close contacts, immunosuppressed); ≥10 mm (high-risk groups, recent immigrants); ≥15 mm (low-risk)
   • Limitations: false positives with BCG vaccination and NTM; false negatives in immunosuppressed patients
2. Interferon-γ Release Assays (IGRAs):
   • QuantiFERON-TB Gold Plus and T-SPOT.TB
   • More specific than TST (not affected by BCG); preferred in BCG-vaccinated individuals
   • Cannot differentiate LTBI from active TB
   • Reduced sensitivity in immunocompromised patients
   • Cannot identify individuals with highest risk of progression

Active TB Diagnosis

1. Sputum microscopy (AFB smear):
   • Rapid, cheap; detects ~5,000-10,000 bacilli/mL
   • Ziehl-Neelsen or fluorochrome staining
   • Sensitivity ~50-80% in pulmonary TB; poor for extrapulmonary/paucibacillary disease
2. Mycobacterial culture:
   • Gold standard; Lowenstein-Jensen medium (solid) or BACTEC/MGIT (liquid)
   • More sensitive; allows drug susceptibility testing (DST)
   • Takes 2-8 weeks (liquid) to 6-8 weeks (solid)
3. Molecular diagnostics (WHO-recommended):
   • Xpert MTB/RIF (GeneXpert): Simultaneous detection of M. tuberculosis and rifampin resistance; results in ~2 hours; endorsed as initial diagnostic test by WHO
   • Line probe assays (LPA): Detect resistance to rifampin and isoniazid (MDR screen)
   • Whole genome sequencing (WGS): Increasingly used for comprehensive resistance profiling and outbreak investigation
4. Imaging: CXR essential; CT chest more sensitive for cavities, miliary pattern, mediastinal nodes

Treatment

Aims of TB Treatment

1. Prevent morbidity and death, cure TB, prevent recurrences and emergence of drug resistance
2. Interrupt transmission by rendering patients noninfectious

Standard Treatment for Drug-Susceptible TB

• Cavitary disease
• 2-month pyrazinamide course not completed
• Sputum cultures positive beyond 2 months (delayed conversion) - also warrants evaluation for resistance

• Daily rifapentine + isoniazid + pyrazinamide + moxifloxacin for 8 weeks, then rifapentine + isoniazid + moxifloxacin for 9 weeks
• Non-inferior to traditional 6-month HRZE - now has conditional WHO recommendation

Treatment of Latent TB Infection (LTBI)

MDR-TB Treatment

• Bedaquiline + pretomanid + linezolid ± moxifloxacin
• Represents a major advance; now endorsed by WHO for pre-XDR and XDR-TB

TB and HIV Co-infection

• HIV is the most powerful risk factor for progression from LTBI to active TB
• TB is the leading cause of death in HIV-positive persons
• CD4+ T cell depletion by HIV explains inability to contain mycobacterial proliferation
• Atypical presentation in advanced HIV: lower lobe disease, hilar adenopathy, absent cavitation, miliary pattern
• Both diseases treated simultaneously; ART initiation: within 2 weeks of starting TB treatment if CD4 <50 cells/μL; within 8-12 weeks if CD4 >50
• Immune reconstitution inflammatory syndrome (IRIS) can occur after ART initiation

Prevention

• BCG vaccination: Protects primarily against disseminated forms (miliary, meningitis) in children; limited efficacy against pulmonary TB in adults; not recommended in immunocompromised patients
• Infection control: Administrative, environmental, and personal protective measures in healthcare settings
• Treatment of LTBI: Most effective tool for elimination strategy
• Contact tracing and screening of high-risk populations