Tuberculosis (TB)

Overview

• Harrison's Principles of Internal Medicine 22E (2025), Ch. 183

Etiologic Agent

Pathogenesis & Immunology

Transmission

Primary Infection and Granuloma Formation

1. Droplet nuclei reach the alveoli and are phagocytosed by alveolar macrophages.
2. M. tuberculosis blocks phagosome maturation (via the type VII secretion system, especially ESX-3 secreting EsxH) and evades intracellular killing.
3. Bacilli multiply locally, eventually spreading via lymphatics to hilar nodes - forming the Ghon complex (peripheral lung focus + hilar lymphadenopathy).
4. Within 2-8 weeks, cell-mediated immunity (CMI) develops: CD4+ Th1 cells produce IFN-γ, activating macrophages to kill bacilli and form granulomas.
5. Granulomas contain the infection. Central caseous necrosis is characteristic of TB.

Outcomes After Primary Infection

• ~90%: Infection contained (latent TB infection, LTBI) - no disease, but the bacteria persist.
• ~10%: Progress to active disease - half within the first 1-2 years, half later in life (reactivation).
• Risk of reactivation is greatly increased by HIV co-infection, malnutrition, diabetes, TNF-α inhibitor therapy, silicosis, and immunosuppression.

Vitamin D and Immunity

• Murray & Nadel's Textbook of Respiratory Medicine

Clinical Manifestations

Pulmonary TB

Primary Disease

• Occurs after initial infection; often in children in high-transmission areas.
• Can be asymptomatic or present with fever and pleuritic chest pain.
• Middle/lower lobes most affected (reflects inhaled air distribution).
• Ghon focus: peripheral lesion + transient hilar lymphadenopathy = Ghon complex.
• Complications: pleural effusion (up to two-thirds of cases), progressive primary TB with cavitation (especially in immunocompromised), miliary TB.

Postprimary (Reactivation) Disease

• Occurs in adults from reactivation of a latent focus or from reinfection.
• Predilection for the apical and posterior segments of upper lobes and superior segments of lower lobes (highest O₂ tension favors bacterial growth).
• Symptoms are typically insidious:
  • Constitutional: fever (often low-grade, afternoon), night sweats, weight loss, fatigue, anorexia.
  • Respiratory: productive cough (often starting dry, then mucopurulent), hemoptysis, dyspnea, pleuritic chest pain.
• Examination: dullness, crackles over involved areas; in extensive disease, signs of consolidation.
• Chest X-ray: upper lobe infiltrates ± cavities ± nodular lesions. Cavities are classic - they indicate high bacterial burden and confer higher infectiousness.

Extrapulmonary TB

Diagnosis

1. Skin Test and IGRA (for LTBI and TB infection)

• Tuberculin Skin Test (TST / Mantoux): Intradermal injection of purified protein derivative (PPD); induration read at 48-72 h. Positive threshold varies: ≥5 mm (HIV+, close contacts, immunosuppressed), ≥10 mm (high-risk groups), ≥15 mm (general population). Limitations: false-positive with BCG vaccination and non-tuberculous mycobacteria; false-negative in severe immunosuppression.
• Interferon-Gamma Release Assays (IGRA): QuantiFERON-TB Gold Plus and T-SPOT.TB. Measure IFN-γ release in response to TB-specific antigens (ESAT-6, CFP-10). More specific than TST (not affected by BCG). Preferred in BCG-vaccinated individuals.

2. Microbiologic Diagnosis (for Active TB)

• AFB Smear Microscopy: Rapid, cheap, but only ~50-60% sensitive in pulmonary TB. Detects ≥5,000-10,000 bacilli/mL. Ziehl-Neelsen or auramine-rhodamine staining.
• Culture: Gold standard. Liquid media (MGIT) is faster (1-3 weeks vs. 3-8 weeks on solid media). Allows drug susceptibility testing (DST).
• Nucleic Acid Amplification (NAAT) - First-line now preferred:
  • Xpert MTB/RIF: Detects M. tuberculosis and rifampin resistance simultaneously in <2 hours. Sensitivity 85% overall (98% smear-positive, ~70% smear-negative); specificity 98%. WHO-recommended as first-line test globally for all adults and children with TB symptoms.
  • Xpert MTB/RIF Ultra: Newer cartridge with improved sensitivity (90%), especially in smear-negative and HIV-positive cases, but slightly lower specificity (96%). "Trace calls" in extrapulmonary specimens, HIV-positive, and children should be considered true positives.
  • Truenat MTB/MTB Plus: Point-of-care alternatives; sensitivities 73-80%.

3. Drug Susceptibility Testing (DST)

• Phenotypic DST: MIC-based culture methods (MGIT-based) - gold standard for DST.
• Molecular DST: Line probe assays (LPA), whole-genome sequencing (WGS) - increasingly used for rapid detection of resistance mutations.

4. Chest Imaging

• CXR: Upper lobe infiltrates, cavities, nodules, hilar lymphadenopathy, pleural effusion, miliary pattern.
• CT chest is more sensitive for detecting subtle lesions, cavities, and endobronchial disease.

5. Extrapulmonary Workup

• CSF analysis (for meningitis): lymphocytic pleocytosis, elevated protein, low glucose; Xpert MTB/RIF Ultra applied to CSF is now the initial preferred test.
• Pleural fluid: exudate, lymphocytic; ADA >40 IU/L strongly suggests TB pleuritis; pleural biopsy has higher yield than fluid culture.
• Adenosine deaminase (ADA): useful in pleural, pericardial, and peritoneal TB.

Treatment

1. Treatment of Latent TB Infection (LTBI)

2. Treatment of Active Drug-Susceptible TB

• Rifapentine + Isoniazid + Pyrazinamide + Moxifloxacin for 8 weeks, then Rifapentine + Isoniazid + Moxifloxacin for 9 weeks.
• Non-inferior to standard 6-month regimen in the multinational TBTC Study 31/ACTG A5349 trial; includes HIV-positive patients with CD4 >100.

2025 ATS/CDC/ERS/IDSA Guideline Update (PMID: 40693952): All-oral, shorter treatment regimens for TB are now recommended for eligible individuals, including a novel 4-month regimen for pulmonary TB and a shortened 4-month regimen for children with non-severe TB.

3. Treatment of Drug-Resistant TB

• Monoresistance: Resistant to one first-line drug only.
• Poly-resistance: Resistant to more than one first-line drug, not including both H and R.
• MDR-TB (Multidrug-resistant): Resistant to at least isoniazid AND rifampin.
• Pre-XDR-TB: MDR/RR-TB + resistance to any fluoroquinolone.
• XDR-TB (Extensively drug-resistant): MDR/RR-TB + resistance to fluoroquinolones + at least one of bedaquiline or linezolid.

• BPaL: Bedaquiline + Pretomanid + Linezolid - for XDR-TB and treatment-intolerant MDR-TB; highly effective all-oral regimen.
• BPaLM: Bedaquiline + Pretomanid + Linezolid + Moxifloxacin - for MDR/RR-TB when fluoroquinolone resistance is absent; 6-month duration.
• These regimens replaced older injectable-based regimens (aminoglycosides).

4. Key Drugs and Adverse Effects

Special Considerations

TB and HIV

• HIV is the most powerful risk factor for TB reactivation. The risk is 20-37x higher in PLWH.
• TB is the leading cause of death in HIV-positive patients worldwide.
• Antiretroviral therapy (ART) should be initiated within 2-8 weeks of starting TB therapy (except in TB meningitis - delay to 8 weeks reduces IRIS-related mortality).
• Rifamycin-antiretroviral drug interactions are significant (rifampin strongly induces CYP3A4, affecting PIs and NNRTIs; rifabutin is preferred with PIs).
• Immune Reconstitution Inflammatory Syndrome (IRIS) can occur 2-8 weeks after ART initiation.

TB in Pregnancy

• Active TB during pregnancy increases maternal and fetal morbidity.
• Standard HRZE regimen is generally safe in pregnancy.
• Streptomycin is contraindicated (ototoxicity to fetus).
• 3HP (isoniazid-rifapentine) for LTBI is not recommended in pregnancy.

BCG Vaccination

• BCG (Bacille Calmette-Guérin) is a live-attenuated M. bovis vaccine.
• Provides approximately 80% protection against severe TB in infants (miliary TB, TB meningitis).
• Recommended at birth in high-incidence countries.
• Does not reliably prevent pulmonary reactivation in adults.
• Can cause false-positive TST results.

Drug Monitoring

• LFTs before and during treatment (monthly if risk factors for hepatotoxicity).
• Visual acuity and color discrimination for ethambutol.
• Serum uric acid for pyrazinamide.
• ECG and QTc for bedaquiline.

Infection Control

• Airborne (droplet nuclei) precautions: N95 respirator, negative pressure isolation room (12 air changes/hour).
• Patient can be considered non-infectious after 3 weeks of effective therapy with clinical improvement and negative sputum smears (though culture may remain positive).
• Contact tracing and testing of all close contacts.

Key Summary

• Harrison's Principles of Internal Medicine, 22nd Edition (2025), Chapters 183 and 186
• Murray & Nadel's Textbook of Respiratory Medicine
• 2025 ATS/CDC/ERS/IDSA Clinical Practice Guideline on TB Treatment (PMID 40693952) - updates treatment to include 4-month regimen for drug-susceptible TB and BPaL/BPaLM for drug-resistant TB