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Tuberculosis (TB) - Clinical Notes

1. Etiology and Transmission

• Caused by Mycobacterium tuberculosis (MTB), an aerobic, acid-fast bacillus
• Transmitted via airborne droplet nuclei from close contact with infectious patients (e.g., household contact with active pulmonary TB)
• Only ~5% of newly infected individuals develop significant disease; 95% are controlled by cell-mediated immunity

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2. Epidemiology

• One of the most common causes of fatal respiratory infection worldwide
• 80% of cases come from 22 high-burden nations
• WHO estimated 8.8 million new cases/year; 1.7 million deaths attributed to TB
• TB in North America was rising in the 1980s but has been declining since 1992
• Multidrug-resistant (MDR) TB is a rising problem: 3% of newly diagnosed cases worldwide; 15% of previously treated cases
• High-risk groups: children, elderly, immunocompromised, HIV-positive, residents of long-term care facilities

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3. Pathogenesis

3a. Primary TB

• Occurs in a previously unexposed, unsensitized patient
• Inhaled bacilli implant in the distal air spaces of the lower part of the upper lobe or upper part of the lower lobe, close to the pleura
• A 1–1.5 cm gray-white consolidation develops - called the Ghon focus - with central caseous necrosis
• Bacilli travel via lymphatics to hilar/regional lymph nodes, which also caseate
• Ghon complex = parenchymal Ghon focus + involved lymph nodes
• After fibrosis and calcification = Ranke complex (visible on X-ray)

• Cell-mediated immunity controls the infection in ~95% of cases
• Progressive primary TB occurs in overtly immunocompromised patients (especially HIV+ with CD4+ <200 cells/μL) - granulomas may be absent; sheets of macrophages packed with bacilli instead

3b. Secondary (Reactivation) TB

• Arises in a previously sensitized host - reactivation of dormant lesions (often decades later) or reinfection
• Classically localized to the apex of one or both upper lobes (possibly due to high O₂ tension)
• Preexisting hypersensitivity → prompt tissue response → walling off of focus
• Less lymph node involvement than primary, but cavitation is common and is a major source of infectivity
• HIV patients with mild immunosuppression (CD4 >300) present with apical cavitary disease; those severely immunocompromised (CD4 <200) present like progressive primary TB

3c. Histopathology

• Caseating granulomas with epithelioid macrophages and Langhans multinucleate giant cells = hallmark
• Even without central caseation, granulomas warrant acid-fast staining for mycobacteria
• Immunocompromised patients: granulomas may be absent - only sheets of macrophages with bacilli

3d. The Three-Population Model of Chemotherapy

1. Actively multiplying extracellular bacilli - targeted by INH (greatest early bactericidal effect)
2. Slowly multiplying in acidic compartments - targeted by PZA
3. Sporadically multiplying bacilli - targeted by rifampin (sterilizing activity)

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4. Clinical Presentation

Pulmonary TB

• Cough, fever, dyspnea, night sweats, anorexia, weight loss, hemoptysis (in ~50%)
• Physical findings: wheezes, rales, signs of consolidation
• Sputum becomes purulent as cavitation occurs
• Low-grade remittent afternoon fever with night sweats is characteristic

Extrapulmonary TB (10–25% of cases worldwide)

1. Disseminated (miliary) TB - lymphohematogenous spread; millet-seed granulomas in liver, spleen, bone marrow, adrenals, meninges, kidneys, fallopian tubes; more common in children and immunosuppressed
2. "Serosal" TB - pleurisy, pericarditis, peritonitis, arthritis with effusion
3. TB of solid organs - osteomyelitis, adrenal TB (Addison disease), renal TB
4. TB lymphadenitis - most frequent extrapulmonary form; usually cervical ("scrofula")
5. TB meningitis - most dangerous serosal form; can cause permanent brain damage; diagnosis difficult
6. Pott disease - vertebral TB; paraspinal "cold" abscesses may present as abdominal/pelvic mass
7. Intestinal TB - ileal involvement common; mucosal ulceration

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5. Diagnosis

Tuberculin Skin Test (TST / PPD)

• BCG-vaccinated patients can still be accurately tested with PPD
• PPD/TST is NOT recommended as routine screening in low-risk populations

Interferon-γ Release Assays (IGRAs)

• QuantiFERON-TB Gold (QFT) and T-SPOT.TB: single-time blood sample; greater specificity for MTB; no anamnestic response on repeat testing; no cross-reaction from BCG
• A positive QFT percentage >15 is moderately correlated with a positive TST in high-risk populations

Sputum Smear & Culture

• AFB smear (acid-fast staining or fluorescent auramine) - most common initial method
• Culture: takes 2–8 weeks standard; rapid methods (liquid media) detect growth in 5–14 days
• Cultures also essential for drug susceptibility testing (DST)
• In infants/young children: gastric aspirates (3 consecutive mornings) + sputum - only ~50% sensitivity

Molecular Tests (PCR / Xpert MTB/RIF)

• PCR sensitivity: 95–98% for smear-positive + culture-positive; 57–78% for smear-negative + culture-positive
• PCR on CSF: multiplex PCR has 94% sensitivity and 100% specificity for culture-confirmed TB meningitis (small series)
• Rapid molecular DST can detect rifampin resistance within hours and is strongly recommended for HIV+ patients

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6. Chest Radiograph Findings

• HIV patients: findings may be atypical; chest X-ray occasionally normal

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7. Latent TB Infection (LTBI)

• Defined by positive TST or IGRA without evidence of active disease
• Treatment options:
  • Isoniazid (INH) x 6–9 months (standard; clinical hepatitis in ~0.6%)
  • Rifampin x 4 months (effective alternative)
  • Rifampin + PZA x 2 months - no longer recommended due to increased liver toxicity
• Treatment indicated even in BCG-vaccinated patients and HIV co-infected patients

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8. Treatment of Active TB

Standard 6-Month Regimen (Drug-Susceptible TB)

• Extended 9-month course indicated for: cavitary lesions OR persistent positive cultures at 2 months
• Repeat cultures after 2 months: 80% should be negative by then
• Daily dosing superior to twice-weekly in RCTs
• Treatment should be supervised by local/state health department

Drug Mechanisms

Directly Observed Therapy (DOT)

• Recommended for patients at high risk of treatment failure due to noncompliance
• RCTs have not clearly shown benefit over traditional public health strategies alone, but enhanced DOT with social supports and incentives is more effective
• WHO reports 82% treatment success rate worldwide

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9. Drug-Resistant TB

• MDR-TB: resistant to at least INH and RIF (the two most potent first-line drugs)
• Cause: inadequate or poorly administered regimens allow resistant mutants to become the dominant strain
• Treatment requires expert consultation and second-line agents (fluoroquinolones, bedaquiline, linezolid, etc.)
• DST should be performed on all previously treated TB patients
• Rapid molecular DST (Xpert MTB/RIF) can detect RIF resistance within hours

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10. HIV and TB

• TB risk elevated at all stages of HIV disease
• CD4+ >300: typical secondary TB (apical, cavitary)
• CD4+ <200: resembles progressive primary TB (lower/middle lobe consolidation, hilar lymphadenopathy, noncavitary); extrapulmonary >50%
• Chest radiographic findings can be atypical or normal
• Rapid molecular DST strongly recommended for all HIV+ TB patients
• Pulmonary TB treated for 6 months regardless of HIV status

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11. Prevention and Control

Infection Control (Four Categories)

1. Clinician awareness and prompt, appropriate responses
2. Administrative controls
3. Environmental controls
4. Personal protective equipment

BCG Vaccine

• Live attenuated Mycobacterium bovis
• Protection estimated at ~50% in meta-analyses
• Decreases severity of disease, especially in children (protective against miliary TB and meningitis)
• Widely used intradermally in high-burden countries

Contact Tracing

• In low-burden countries: evaluate contacts, treat highest-risk contacts for LTBI
• Community-wide Xpert screening in high-burden settings reduced TB prevalence by 44% in one cluster-randomized trial

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12. Key Summary Points

• 80% of TB comes from 22 high-burden nations
• Sputum cultures confirm diagnosis AND identify drug resistance; PCR provides faster results
• Latent infection (positive TST, normal CXR, asymptomatic): treat with INH x 6–9 months or RIF x 4 months
• Active pulmonary TB: RIPE x 2 months → IR x 4 months (total 6 months)
• Cavitary lesion or culture-positive at 2 months → extend to 9 months
• Extrapulmonary sites in order of frequency: lymph nodes > pleura > genitourinary > bone/joint > meningitis
• MDR-TB is defined by resistance to both INH and rifampin; requires expert management

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