Pulmonary Tuberculosis

Overview

Spectrum of TB Infection

Spectrum of outcomes after TB infection - from Goldman-Cecil Medicine

Pathogenesis

1. Inhalation - Droplet nuclei carrying M. tuberculosis are inhaled and reach the alveoli.
2. Macrophage uptake - Alveolar macrophages phagocytose the bacilli, but the organism resists intracellular killing by inhibiting phagosome-lysosome fusion.
3. Granuloma formation - T-cell mediated immunity triggers formation of granulomas (caseating necrosis at center, surrounded by epithelioid macrophages, Langhans giant cells, and lymphocytes). This is the hallmark lesion - the tubercle.
4. Ghon focus - The primary parenchymal lesion, typically in the lower/middle lung zones where ventilation is highest.
5. Ghon complex - Ghon focus + ipsilateral hilar lymph node enlargement.
6. Reactivation - If cell-mediated immunity wanes (HIV, malnutrition, diabetes, TNF-alpha inhibitors, aging), dormant organisms reactivate, typically in the upper lobes (high oxygen tension).

Clinical Features

Symptoms

• Cough (most common symptom - productive or dry; up to 25% of culture-confirmed cases have no cough)
• Fever and night sweats
• Weight loss and anorexia
• Fatigue and malaise
• Hemoptysis - occurs with more extensive or cavitary disease; may also result from a Rasmussen aneurysm (dilated vessel in an old cavity wall) or aspergilloma in a residual cavity

Physical Examination

• Post-tussive rales in the upper lung zones
• Amphoric breath sounds (suggesting a cavity)
• Lymphadenopathy (more common in HIV-infected patients)
• Laboratory: leukocytosis and anemia may be present

Disease Classification

• Progressive primary TB - Active disease occurring within the first year of initial infection
• Reactivation (post-primary) TB - Disease arising from dormant organisms, typically in the apical-posterior segments of upper lobes

Radiology

Chest X-ray and CT Findings

• Primary TB: Middle/lower zone infiltrates, hilar lymphadenopathy (Ghon complex), pleural effusion
• Reactivation TB: Upper lobe infiltrates, cavitation (apical-posterior segments), fibrosis, calcified nodules
• Miliary TB: Diffuse 1-2 mm nodules throughout both lung fields (classic "millet seed" pattern, seen in ~85%)
• Cavitation indicates high bacillary burden and increased infectivity

CT chest showing TB lymphadenopathy and parenchymal lesion - Goldman-Cecil Medicine

TB in HIV-Infected Patients

• Manifestations depend on degree of immune dysfunction
• Less likely to be smear-positive or have cavitary disease
• More likely to develop disseminated infection
• May have normal chest X-ray despite smear-positive disease - CT is more sensitive
• In advanced AIDS with miliary TB, blood cultures may be positive in 20-40% of cases

Extrapulmonary Manifestations

Pleural TB

• Occurs 3-6 months after primary infection
• Exudative unilateral pleural effusion
• Cough, pleuritic chest pain, systemic symptoms

Miliary TB

• 1-2 mm granulomatous nodules in lungs, liver, bone marrow, kidneys, adrenal glands, spleen
• Choroidal tubercles on fundoscopy (pathognomonic when seen)
• Fever, weight loss, night sweats without localizing symptoms

Diagnosis

1. Sputum Examination

• At least two sputum specimens for AFB smear + mycobacterial culture (three is standard in the US)
• At least one specimen for Nucleic Acid Amplification Testing (NAAT)

2. Nucleic Acid Amplification Testing (NAAT)

• Xpert MTB/RIF (GeneXpert): Automated, self-contained real-time PCR that simultaneously detects M. tuberculosis DNA and rifampin resistance in 90 minutes
• WHO-recommended as the preferred initial test for HIV-infected patients, suspected drug-resistant TB, and seriously ill patients
• Sensitivity ~89% for smear-positive, ~67% for smear-negative pulmonary TB
• A negative NAAT does not exclude active disease - culture is still required in smear-negative suspects

• Smear-positive + NAAT-positive: Rapid confirmation of TB
• Smear-positive + NAAT-negative: Suggests NTM (not TB)
• Smear-negative + NAAT-positive (intermediate-high clinical probability): Presumptive TB
• Smear-negative + NAAT-negative: Does not exclude TB; culture still required

3. Testing for Latent TB Infection (LTBI)

• Intradermal injection of 5 tuberculin units PPD; read at 48-72 hours
• Cut-points for positivity based on risk:
  • ≥5 mm: HIV infection, close contacts of active TB, organ transplant/immunosuppressed, fibrotic changes on CXR
  • ≥10 mm: Recent immigrants from high-incidence countries, injection drug users, healthcare workers, prisoners, clinical conditions (diabetes, silicosis, CKD)
  • ≥15 mm: Low-risk persons
• Limitations: False-positive with BCG vaccination or NTM exposure; false-negative in immunosuppressed patients; booster phenomenon with serial testing

• QuantiFERON-TB Gold Plus and T-SPOT.TB
• Blood-based; measures IFN-γ release in response to TB-specific antigens (ESAT-6, CFP-10)
• Preferred over TST in persons with BCG vaccination history
• Not affected by BCG; more specific than TST

• Birth/residence in high-incidence country (>10/100,000/year)
• Close contact with infectious TB case
• HIV infection
• Planned immunosuppression (organ transplant, TNF-alpha antagonists, corticosteroids ≥15 mg/day for ≥1 month)
• Homelessness, incarceration, healthcare workers

Treatment

Infectivity and Isolation

• At least 2 weeks of therapy
• Clinical improvement (reduced cough, weight gain, fever resolution)
• No detectable AFB on three sputum specimens at least 8 hours apart

Drug-Susceptible TB (Standard Regimen)

First-Line Drug Doses (Adults)

Important Ancillary Points

• Pyridoxine (Vitamin B6) 25-50 mg/day should be given with isoniazid to prevent peripheral neuropathy (especially in diabetics, alcoholics, HIV-positive, pregnant women, malnourished patients)
• Rifampin: potent CYP inducer - significant drug interactions (oral contraceptives, anticoagulants, antiretrovirals)
• Ethambutol: causes dose-dependent optic neuritis - baseline and monthly visual acuity/color vision testing required
• Pyrazinamide: causes hyperuricemia and hepatotoxicity; avoid in severe hepatic disease
• Drug susceptibility testing should be performed on all isolates

Follow-Up

• Monthly clinical assessment + sputum examination until two consecutive negative cultures
• 75-80% of pulmonary TB patients are sputum culture-negative by 2 months
• ~95% are culture-negative by 3 months
• Positive culture at 4 months = treatment failure (rare in properly treated drug-sensitive disease) - prompts expert consultation
• Never add a single drug to a failing regimen - this promotes further resistance

Latent TB Infection (LTBI) Treatment Regimens

Drug-Resistant TB

Definitions

• Rifampin resistance on Xpert MTB/RIF strongly correlates with MDR-TB
• MDR-TB and XDR-TB require longer regimens (18-24+ months) using second-line drugs including bedaquiline, linezolid, clofazimine, cycloserine, delamanid, and pretomanid

Complications

• Massive hemoptysis (Rasmussen aneurysm rupture)
• Pneumothorax (from subpleural cavity rupture)
• Aspergilloma (fungus ball in old residual cavity)
• Bronchiectasis (from fibrosis and airway distortion)
• Cor pulmonale (from extensive pulmonary fibrosis)
• Disseminated/miliary TB (hematogenous spread)
• ARDS (in severe disease)

Public Health Considerations

• TB is a notifiable disease - local health departments must be notified
• Contact tracing and testing of close contacts is mandatory
• Directly Observed Therapy (DOT) is the standard of care to ensure adherence
• In the US, expert guidance is available through the 4 regional TB Centers of Excellence (CDC-funded) covering all 50 states