Tuberculosis (Active and Latent)
Mycobacterium tuberculosis infection — active disease or asymptomatic latent infection (LTBI).
Also known as: TB, tuberculosis, latent TB, LTBI, active TB, Mycobacterium tuberculosis, miliary TB
Overview
Infection with Mycobacterium tuberculosis complex. Latent TB infection (LTBI): asymptomatic, non-contagious, positive immunologic test, no clinical/radiographic disease. Active TB: symptomatic disease, often pulmonary, contagious; may be primary or reactivation.
Epidemiology
Globally ~10 million new cases and ~1.3 million deaths annually. In the US, >85% of cases occur in non-US-born persons or those born in high-burden countries. HIV coinfection accelerates progression. Drug-resistant TB (MDR, XDR) is a global challenge.
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Risk factors
- Birth or residence in high-prevalence country, recent travel
- Close contact with active pulmonary TB case
- HIV/AIDS, immunosuppression (TNF-alpha inhibitors, transplant, chemotherapy, chronic corticosteroids)
- Diabetes mellitus, end-stage renal disease, silicosis
- Healthcare workers, prison/shelter exposure, IV drug use
- Children <5 years and elderly
- Malnutrition, alcohol use disorder, smoking
Pathophysiology
Inhaled aerosolized droplet nuclei reach alveoli, ingested by alveolar macrophages. Most contain infection in granulomas (latent). With reduced immunity, dormant bacilli reactivate → caseating granulomas, cavitation, hematogenous spread (miliary). Lifetime reactivation risk ~5-10% (general), ~10%/year with untreated HIV.
Clinical presentation
Symptoms
- LTBI: asymptomatic by definition
- Active pulmonary TB: chronic cough >3 weeks (productive, may be hemoptysis), drenching night sweats, fevers, weight loss, anorexia, fatigue
- Pleuritic chest pain if pleural involvement
- Extrapulmonary TB: lymphadenitis (scrofula), TB meningitis, Pott disease (spinal), genitourinary, peritoneal, miliary
Signs / physical exam
- Often nonspecific exam early in disease
- Fever, cachexia, post-tussive crackles, amphoric breath sounds over cavities
- Lymphadenopathy, hepatosplenomegaly (miliary)
Classic findings
Apical/posterior upper lobe or superior segment of lower lobe cavitary disease (reactivation); hilar lymphadenopathy + middle/lower lobe infiltrate (primary); miliary nodules (2-3 mm) on CXR (disseminated).
Differential diagnosis
- Community-acquired pneumonia — Acute onset, lobar consolidation, responds to standard antibiotics within days
- Lung cancer — Mass lesion in smoker, weight loss, hemoptysis; biopsy distinguishes
- Non-tuberculous mycobacteria (M. avium complex, M. kansasii) — Older women with bronchiectasis ('Lady Windermere'), cavitary disease in COPD; AFB+ but TB-specific NAAT negative
- Fungal pneumonia (histoplasmosis, coccidioidomycosis, blastomycosis) — Geographic exposure (Mississippi/Ohio valley, Southwest, Great Lakes); serology and fungal cultures
- Sarcoidosis — Bilateral hilar lymphadenopathy without parenchymal cavitation, non-caseating granulomas, elevated ACE
- Lung abscess — Air-fluid level on CXR, putrid sputum, polymicrobial flora
- Pulmonary aspergillosis — Aspergilloma in pre-existing cavity (often TB), positive Aspergillus IgG/galactomannan
Diagnostic workup
Diagnostic criteria
LTBI: positive TST (induration ≥5/10/15 mm cutoff based on risk) or positive IGRA + no active disease on imaging/clinical evaluation. Active TB: clinical findings + positive AFB smear/NAAT/culture from respiratory or other site.
Labs
- LTBI: tuberculin skin test (TST/PPD) OR interferon-gamma release assay (IGRA — QuantiFERON, T-SPOT)
- Active TB: 3 sputum samples for AFB smear, culture (gold standard, 6-8 weeks), and NAAT (Xpert MTB/RIF, rapid)
- HIV test on every TB patient
- CBC, CMP, hepatitis serologies, baseline LFTs before treatment
- Drug susceptibility testing on positive culture
Imaging
- CXR — primary: hilar adenopathy, middle/lower infiltrate, Ghon complex; reactivation: apical/posterior cavitary lesions; miliary: 2-3 mm nodules diffuse
- CT chest if CXR equivocal or to characterize disease
- MRI brain/spine if neurologic/spinal TB suspected
Diagnostic algorithm
| TST Induration | Considered Positive If… |
|---|---|
| ≥5 mm | HIV+, recent contact with active TB, fibrotic CXR consistent with prior TB, organ transplant, immunosuppression (≥15 mg/d prednisone × 1 mo, TNF inhibitors) |
| ≥10 mm | Recent immigrant (<5 y) from high-prevalence country, IVDU, healthcare workers, prison/shelter residents, children <5, mycobacterial lab workers, diabetes/CKD/silicosis |
| ≥15 mm | Any person with no known risk factors |
Treatment
First-line
- LTBI (CDC 2020 preferred shorter regimens): isoniazid + rifapentine weekly × 12 weeks (3HP, DOT); OR rifampin daily × 4 months (4R); OR isoniazid + rifampin daily × 3 months (3HR)
- LTBI alternative: isoniazid daily × 6 or 9 months (older standard; longer, more hepatotoxicity)
- Active drug-susceptible TB (RIPE × 2 months intensive phase): rifampin (R) + isoniazid (H/INH) + pyrazinamide (Z/PZA) + ethambutol (E)
- Continuation phase × 4 months: rifampin + isoniazid (HR) — total 6 months
- Always add pyridoxine (vitamin B6) 25-50 mg daily with isoniazid to prevent peripheral neuropathy
- Directly observed therapy (DOT) recommended to ensure adherence and prevent resistance
- Report all cases to public health department; contact tracing
Second-line / adjunct
- Drug-resistant TB: MDR (resistant to INH + RIF) — bedaquiline-containing regimens (BPaL: bedaquiline + pretomanid + linezolid × 6 months, per 2022 WHO update)
- XDR (additional resistance to fluoroquinolones and a second-line injectable): individualized regimens with newer agents
- TB meningitis: extend therapy to 9-12 months + adjunctive corticosteroids (dexamethasone) to reduce mortality and neurologic sequelae
- Pott disease (spinal TB): 6-9 months + surgical consultation for spinal instability or cord compression
- HIV coinfection: start ART within 2-8 weeks of TB therapy (sooner if CD4 <50); watch for IRIS
- Drug toxicities: hepatotoxicity (especially INH, RIF, PZA — monitor LFTs), optic neuritis (ethambutol — baseline and monthly vision), hyperuricemia/gout (PZA), orange body fluids (rifampin), drug-drug interactions (rifampin is potent CYP3A4 inducer)
Complications
- Cavitary disease, hemoptysis (Rasmussen aneurysm), pneumothorax
- Miliary/disseminated TB, TB meningitis, Pott disease
- Multidrug-resistant and extensively drug-resistant TB
- Aspergilloma formation in old cavities
- Constrictive pericarditis, bronchiectasis (post-TB)
- Drug toxicities — DILI, peripheral neuropathy, optic neuritis
PANCE pearls
- Reactivation TB favors apical/posterior segments (higher O2 tension); primary TB favors middle/lower lobes with hilar adenopathy.
- Mantoux interpretation: ≥5 mm positive if HIV, recent contact, immunosuppressed, fibrotic CXR; ≥10 mm if high-risk demographic; ≥15 mm for low-risk patients.
- IGRA preferred over TST in BCG-vaccinated individuals (BCG can cause false-positive TST).
- Rifampin turns body fluids orange and is a potent CYP3A4 inducer — reduces efficacy of OCPs, warfarin, ART, statins, and many others.
- Pregnancy: use RIPE without streptomycin (ototoxic to fetus); pyridoxine essential. Treat LTBI in pregnant women only if recent infection or HIV+; otherwise defer postpartum.
References
- CDC/IDSA/NTCA 2020 — Guidelines for the Treatment of Latent Tuberculosis Infection (Sterling et al., MMWR 2020)
- ATS/CDC/IDSA 2016 — Treatment of Drug-Susceptible Tuberculosis (Nahid et al., Clin Infect Dis 2016)
- WHO 2022 — WHO Consolidated Guidelines on Tuberculosis: Drug-Resistant TB Treatment (2022 Update)
- Nix-TB / ZeNix Trials — Bedaquiline-Pretomanid-Linezolid for Highly Drug-Resistant TB (Conradie et al., NEJM 2020/2022)
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