Tuberculosis¶
Chapter 183 | Harrison's 22e · Part 5 – Infectious Diseases: Bacterial · Chapter 183
Key Clinical Points¶
- TB is a leading cause of infectious mortality globally, with ~1.5 million deaths annually.
- M. tuberculosis is an acid-fast bacillus with a complex cell wall (high mycolic acid content) providing resistance to many antibiotics and facilitating immune evasion.
- Transmission occurs via airborne droplet nuclei from pulmonary TB cases.
- Drug-susceptible TB is curable with 6-month regimens; MDR-TB requires 9-20 months of multidrug therapy.
- Latent TB infection (LTBI) affects ~1/3 of the world's population and can progress to active disease if untreated.
- Genitourinary TB often presents with nonspecific urinary symptoms and may cause irreversible renal damage.
- HIV co-infection significantly increases TB mortality rates and complicates management.
- Sputum AFB smear has 20-40% sensitivity; NAAT (e.g., Xpert MTB/RIF) allows rapid detection of MDR-TB in ~2 hours.
- MDR-TB treatment requires ≥4 second-line drugs, including agents such as bedaquiline and linezolid.
- Prevention includes BCG vaccination (50-80% efficacy in children) and LTBI treatment (3HP or 4HR).
1. DEFINITION & OVERVIEW¶
• Definition (Harrison's 22e): Tuberculosis is an infectious disease caused by Mycobacterium tuberculosis, characterized by granulomatous inflammation primarily affecting the lungs but capable of involving any organ. • Pathogen Characteristics: ◦ Acid-fast bacilli: High mycolic acid content in cell wall. ◦ Clinical Impact: Provides resistance to many antibiotics and facilitates immune evasion.
1.1 Etiology¶
• M. tuberculosis complex: Includes 8 subgroups; M. tuberculosis (sensu stricto) is the primary human pathogen. • Related Species: ◦ M. africanum (West/Central/East Africa) ◦ M. bovis (Zoonotic; pyrazinamide resistant) ◦ M. caprae ◦ Rare isolates: M. pinnipedii, M. mungi, M. orygis, M. microti, M. canetti • Table 1: Risk Factors for Active Tuberculosis in Persons Who Have Been Infected with Tubercle Bacilli ◦ High Relative Risk: ◦ HIV infection (21-30) ◦ Silicosis (30) ◦ Jejunoileal bypass (30-60) ◦ Posttransplantation period (20-70) ◦ Moderate Risk: ◦ Chronic renal failure/hemodialysis (10-25) ◦ Immunosuppressive treatment (10) ◦ IV drug use (10-30) ◦ Lower Relative Risk: ◦ Tumor necrosis factor α inhibitors (4-5) ◦ Gastrectomy (2-5) /// ◦ Diabetes (2-4) ◦ Excessive alcohol use (3) ◦ Malnutrition and severe underweight (2)
2. EPIDEMIOLOGY¶
• Global Burden: ◦ ~1.5 million deaths annually. ◦ 90% of cases occur in low/middle-income countries. ◦ HIV co-infection accounts for 13% of TB deaths globally. • Regional Incidence (2022): ◦ Southeast Asia: 350/100,000 ◦ Africa: 280/100,000 • United States Data: ◦ 8,300 cases (2.5/100,000) ◦ 71% among non-US born individuals. ◦ Highest incidence in adults ≥65 years and children <14 years. ◦ Non-Hispanic Black population accounted for 34% of US cases. • Transmission Dynamics: ◦ Airborne transmission via droplet nuclei from pulmonary TB patients. ◦ Risk Factors: Crowded living, HIV (20-30x risk), Diabetes mellitus, Alcohol use disorder. • Epidemiological Mapping: ◦ Figure 2 & 3: Illustrate global distribution of incidence and mortality in HIV-negative populations. ◦ Figure 11 & 12: Highlight the overlap with HIV and the geographic prevalence of MDR-TB.
3. CLINICAL MANIFESTATIONS¶
• Pulmonary Disease (85% of cases): ◦ Primary TB: Lymphadenopathy (hilar/paratracheal), pleural effusion. ◦ Post-primary TB: Cavitary lesions, hemoptysis, weight loss. ◦ Radiographic Findings: ◦ Primary complex: Right upper lobe infiltration with hilar lymphadenopathy (Fig. 1, Fig. 5). ◦ Post-primary disease: Upper lobe cavities with air-fluid levels (Fig. 4, Fig. 7). ◦ Progressive fibrocavitary disease: Lobar hyperinflation from ball-valve effect. ◦ Miliary TB: Disseminated microabscesses; characterized by "millet-sized" infiltrates in both lungs (Fig. 6). • Extrapulmonary Disease (15% of cases): ◦ Genitourinary TB: 50% have concurrent urinary tract involvement; presents with dysuria, hematuria, flank pain; can cause irreversible renal damage (Fig. 10). ◦ Spinal TB (Pott's disease): Back pain, kyphosis, neurological deficits; characterized by vertebral destruction (Fig. 9). ◦ Lymphadenitis: Cervical node involvement (e.g., in pediatric patients) (Fig. 8).
4. DIAGNOSTIC APPROACH¶
- Imaging: ◦ Chest radiography is the initial modality. ◦ Primary: Right upper lobe infiltration with hilar lymphadenopathy. ◦ Post-primary: Upper lobe cavities with air-fluid levels. ◦ Miliary: Diffuse miliary pattern in both lungs.
- Microbiological Testing: ◦ Sputum AFB smear: Sensitivity 20-40% for smear-positive cases. ◦ Nucleic acid amplification tests (NAAT): e.g., Xpert MTB/RIF detects MDR-TB in ~2 hours. ◦ Culture: Gold standard; required for drug susceptibility testing (DST); takes 4-8 weeks.
- Latent TB Detection: ◦ Interferon-gamma release assays (IGRAs).
- Molecular Typing: Used for outbreak investigation.
5. TREATMENT & MANAGEMENT¶
- Drug-Susceptible TB Treatment: ◦ Standard: 6-month regimen (2HRZE/4HRE). ◦ Table 2 Dosages: ◦ Isoniazid: Adult 5 mg/kg (max 300mg) or 10 mg/kg (max 600mg); Pediatric 10 mg/kg (7-15 mg/kg), max 300mg. ◦ Pyrazinamide: Adult 25 mg/kg (max 2g) or 15 mg/kg; Pediatric 35 mg/kg (30-40 mg/kg). ◦ Rifampin: Adult 10 mg/kg; Pediatric 10 mg/kg. ◦ Table 4 Regimens: ◦ New drug-susceptible pulmonary or extrapulmonary cases: ◦ Option A: 2 months HRZE → 4 months HR ◦ Option B: 2 months HPMZ \10 2 months HR ◦ New non-severe pulmonary TB in children/adolescents (3mo-16yr): ◦ Option A: 2 months HRZ(E) → 2 months HR ◦ Option B: 2 months HRE → 7 months HR ◦ Intolerance to Z: 2 months HRE → 7 months HR. ◦ Resistance (or intolerance) to H: Throughout (6 months) RZELf.
- MDR-TB Management: ◦ Duration: 9-20 month regimen. ◦ Requirement: ≥4 second-line drugs (e.g., bedaquiline, delamanid, linezolid). ◦ Table 3 Drug Groups: ◦ Group A: Levofloxacin or moxifloxacin, Bedaquiline, Linezolid. ◦ Group C: Ethambutol, Delamanid, Pyrazinamide, Imipenem-cilastatin/meropenem, Amikacin (or streptomycin), Ethionamide/prothionamide, p-Aminosalicylic acid.
- HIV Co-infection Management: ◦ ART must be initiated within 2 weeks of starting TB treatment.
6. PREVENTION & CONTROL¶
- Vaccination: ◦ BCG vaccination: 50-80% efficacy against severe childhood TB.
- Latent TB Infection (LTBI) Treatment: ◦ Regimens: 3HP (3 months isoniazid + pyrazinamide) or 4HR (4 months rifampin).
- Preventive Treatment Options (Table 6): ◦ Isoniazid alone: 6-9 months. ◦ Isoniazid plus rifampin: 3 months (Adults 10 mg/kg; Children 15 mg/kg [range 10-20 mg/kg]). ◦ Rifapentine plus isoniazid: 1 month (Age >13 only; Isoniazid 300mg, Rifapentine 600mg daily).
- Tuberculin Reaction Cutoffs (Table 5): ◦ HIV-infected, Organ transplant, or Immunosuppressed: ≥5 mm. ◦ High-risk settings/Immigrants (≤5 years): ≥10 mm. ◦ Low-risk persons: ≥15 mm.
KEY PEARLS & HIGH-YIELD POINTS¶
• Acid-Fastness: Due to high mycolic acid; essential for diagnosis via Ziehl-Neelsen stain. • MDR-TB Definition: Resistance to both Isoniazid and Rifampin. • Rapid Diagnosis: NAAT (Xpert) is the preferred method for rapid MDR detection. • Sputum Sensitivity: Only 20-40% of cases are smear-positive; clinical suspicion must remain high. • Pott's Disease: Characterized by spinal destruction and potential neurological compromise. • Miliary TB: Indicates hematogenous spread; often seen in immunocompromised or pediatric patients.
Reference Tables¶
TABLE 183-1 Risk Factors for Active Tuberculosis in Persons Who Have Been Infected with Tubercle Bacilli FACTOR Recent…¶
Harrison's 22e, p.1383
| FACTOR | RELATIVE RISK/ODDSa |
|---|---|
| Recent infection (<1 year) | 12.9 |
| Comorbidities and iatrogenic causes | |
| HIV infection | 21–>30 |
| Silicosis | 30 |
| Chronic renal failure/hemodialysis | 10–25 |
| Diabetes | 2–4 |
| IV drug use | 10–30 |
| Excessive alcohol use | 3 |
| Immunosuppressive treatment | 10 |
| Tumor necrosis factor α inhibitors | 4–5 |
| Gastrectomy | 2–5 |
| Jejunoileal bypass | 30–60 |
| Posttransplantation period (renal, cardiac) | 20–70 |
| Malnutrition and severe underweight | 2 |
TABLE 183-2 Recommended Dosage a for Initial Treatment of Tuberculosis in Adults and Children DRUG Isoniazid Rifampin…¶
Harrison's 22e, p.1394
| DRUG | DAILY DOSE | |
|---|---|---|
| ADULT | PEDIATRIC | |
| Isoniazid | 5 mg/kg, max 300 mg | 10 (7–15) mg/kg, max 300 mg |
| 10 mg/kg, max 600 mg | ||
| Pyrazinamide | 25 mg/kg, max 2 g | 35 (30–40) mg/kg |
| 15 mg/kg |
TABLE 183-3 Groups of Drugs Recommended for Use in Longer MDR-TB Regimens and Approach to the Design of a Longer…¶
Harrison's 22e, p.1394
| GROUP | DRUG |
|---|---|
| Group A: All three drugs should be included to ensure that at least four likely effective agents (including one from group B below) are started and at least three are included for the rest of treatment if bedaquiline is stopped |
Levofloxacin or moxifloxacin |
| Bedaquiline | |
| Linezolid | |
| Group C: Drugs to be used to complete the regimen and when drugs from groups A and B cannot be useda |
Ethambutol Delamanid Pyrazinamide Imipenem-cilastatin or meropenem Amikacin (or streptomycin if amikacin is not available) Ethionamide or prothionamideb p-Aminosalicylic acidb |
TABLE 183-4 Recommended Antituberculosis Treatment Regimens INDICATION New drug-susceptible pulmonary or extrapulmonary…¶
Harrison's 22e, p.1395
| INDICATION | INITIAL PHASE | CONTINUATION PHASE | ||
|---|---|---|---|---|
| DURATION, MONTHS | DRUGS | DURATION, MONTHS | DRUGS | |
| New drug-susceptible pulmonary or extrapulmonarya TB cases | 2 | HRZEb | 4 | HRb,c |
| 2 | HPMZb,d | 2 | ||
| New non-severee TB in children and adolescents aged 3 months to 16 years |
2 | HRZ(E)b | 2 | HRb |
| 2 | HREf | 7 | ||
| Intolerance to Z | 2 | HRE | 7 | HR |
| Resistance (or intolerance) to H | Throughout (6) | RZELfx |
TABLE 183-5 Tuberculin Reaction Size and Cutoff for Tuberculosis (TB) Preventive Treatment¶
Harrison's 22e, p.1401
| RISK GROUP | TUBERCULIN REACTION SIZE, mm |
|---|---|
| HIV-infected persons | ≥5 |
| Organ transplant recipients | ≥5 |
| Persons who are immunosuppressed—e.g., due to the use of glucocorticoids or tumor necrosis factor α inhibitors |
≥5 |
| Recent immigrants (≤5 years) from high-prevalence countries |
≥10 |
| Mycobacteriology laboratory personnel; residents and employees of high-risk congregate settingsc |
≥10 |
| Low-risk personsd | ≥15 |
TABLE 183-6 Recommended Regimens and Drug Dosages for Tuberculosis Preventive Treatment a REGIMEN Isoniazid alone for 6…¶
Harrison's 22e, p.1402
| REGIMEN | DOSE | ADVERSE EVENTS |
|---|---|---|
| Isoniazid alone for 6 or 9 months |
Adults: 5 mg/kg (max, 300 mg) per day Children <10 years of age: 10 mg/kg per day (range, 7–15 mg) |
Drug-induced liver injury, nausea, vomiting, abdominal pain, skin rash, peripheral neuropathy, dizziness, drowsiness, seizure |
| Adults and children: Isoniazid: 15 mg/kg (900 mg) weekly Rifapentine: 15–30 mg/kg (900 mg) weekly |
||
| Isoniazid plus rifampin for 3 months |
As below | As above |
| Adults: 10 mg/kg per day Children <10 years of age: 15 mg/kg (range, 10–20 mg) per day |
||
| Rifapentine plus isoniazid for 1 month |
Age >13 years only: isoniazid 300 mg and rifapentine 600 mg daily (28 doses) |
Essentially similar to those of rifapentine plus isoniazid for 3 months with neutropenia more common and elevation in liver enzyme levels and neuropathy less common |
| Daily: adults 10–15 mg/kg; children 15–20 mg/kg (maximum 750 mg) |