Tuberculosis
A board-focused tuberculosis lesson spanning pathophysiology (caseating granulomas, latent vs. reactivation disease), classic vignettes with next-best-step diagnosis (sputum AFB/NAAT/culture, TST-IGRA cutoffs, imaging), and RIPE-based management with drug toxicities. Targets STEP 1 mechanisms and STEP 2 CK decision-making.
Pathophysiology
Mycobacterium tuberculosis is an aerobic, acid-fast bacillus with a mycolic-acid–rich (waxy) cell wall, spread by inhaled droplet nuclei. Bacilli land in well-ventilated lower/mid-lung zones and are phagocytosed by alveolar macrophages, which they survive by blocking phagolysosome fusion (sulfatides). Over ~3 weeks a Th1 response matures: macrophages present antigen, CD4 T cells release IFN-γ, and TNF-α activates macrophages to wall off bacilli in caseating granulomas — epithelioid histiocytes plus Langhans giant cells (a type IV hypersensitivity reaction, the basis of a positive PPD).
The subpleural Ghon focus + draining hilar node = Ghon complex; when fibrocalcified = Ranke complex. Most people contain infection as latent TB (viable but dormant bacilli — asymptomatic, non-infectious, positive PPD/IGRA). Reactivation occurs when cell-mediated immunity wanes (HIV, aging, TNF-α inhibitors, steroids, malnutrition), classically in the oxygen-rich apical/posterior upper lobes.
- Microbiology: acid-fast (Ziehl-Neelsen/auramine-rhodamine); slow-growing on Löwenstein-Jensen; cord factor (trehalose dimycolate) = virulence (induces TNF-α, granuloma formation); sulfatides block phagolysosome fusion.
- Primary TB: mid/lower-lobe consolidation + hilar adenopathy (Ghon complex); usually asymptomatic → latent.
- Reactivation (secondary) TB: apical/posterior upper-lobe cavitation; fever, drenching night sweats, weight loss, chronic cough ± hemoptysis.
- Miliary TB: hematogenous spread → diffuse millet-seed micronodules; seeds liver, spleen, marrow, meninges, adrenals.
- Extrapulmonary: Pott disease (vertebral), scrofula (cervical lymphadenitis), TB meningitis (basilar), renal (sterile pyuria), adrenal (Addison).
- Labs: anemia of chronic disease, SIADH (hyponatremia), hypercalcemia (granuloma 1α-hydroxylase → calcitriol).
- TNF-α maintains granulomas → anti-TNF biologics reactivate latent TB (screen first).
A 34-year-old man who emigrated from India 2 years ago has 6 weeks of productive cough, drenching night sweats, 5-kg weight loss, and one episode of hemoptysis. Temp 38.1°C. CXR shows a right-upper-lobe cavitary infiltrate.
Next best step: place him in a negative-pressure airborne-isolation room and collect 3 sputum samples for AFB smear + mycobacterial culture, plus a NAAT (Xpert MTB/RIF) — before empiric therapy.
- Culture = gold standard (also gives drug susceptibility); NAAT confirms rapidly and detects rifampin resistance.
- Do not use TST/IGRA to diagnose active disease — they indicate infection/exposure, not activity.
- Report to the public health department (mandatory), initiate contact tracing, and start RIPE under directly observed therapy (DOT) once TB is confirmed or highly suspected.
- Imaging: upper-lobe cavitation (reactivation); calcified Ghon/Ranke complex; miliary micronodules; tree-in-bud on CT = endobronchial spread. In advanced HIV/immunocompromised the picture is atypical — lower-lobe disease, adenopathy, less cavitation.
- Microbiology: sputum AFB smear (rapid, low sensitivity) → NAAT → culture on Löwenstein-Jensen (gold standard, slow 2–6 wk).
- Latent TB screening — TST (PPD) or IGRA: IGRA (QuantiFERON) preferred if BCG-vaccinated (BCG causes false-positive TST). Positive test + normal CXR + no symptoms = latent TB.
- Always get a CXR before treating a positive TST/IGRA to exclude active disease.
- PFTs: not diagnostic; chronic/healed TB may cause restriction (fibrosis) or obstruction/bronchiectasis from architectural destruction.
Latent vs. Active TB
| Feature | Latent TB | Active TB |
|---|---|---|
| Symptoms | None | Cough, fever, night sweats, weight loss |
| Infectious? | No | Yes (pulmonary) |
| CXR | Normal (± calcified granuloma) | Infiltrate / cavity / adenopathy |
| Sputum AFB & culture | Negative | Positive |
| TST / IGRA | Positive | Positive (not used to confirm) |
| Treatment | 3HP, 4R, or 3HR (rifamycin-based) | RIPE ×2 mo → RH ×4 mo |
TST (PPD) Positive Cutoffs
| Induration | Considered positive in… |
|---|---|
| ≥ 5 mm | HIV; recent TB contact; fibrotic CXR (old TB); organ transplant / immunosuppressed (≥15 mg/d prednisone, anti-TNF) |
| ≥ 10 mm | Immigrants (<5 yr) from high-prevalence areas; IV drug users; healthcare / prison / shelter workers; mycobacteriology lab staff; children <4 yr; DM, silicosis, CKD, leukemia |
| ≥ 15 mm | Persons with no risk factors |
RIPE = the 4-drug intensive-phase regimen for active TB:
- Rifampin → orange/red body fluids (harmless), hepatotoxic, potent CYP450 inducer (↓ OCPs, warfarin).
- Isoniazid (INH) → peripheral neuropathy (give pyridoxine/B6), hepatotoxicity, drug-induced lupus; CYP450 inhibitor.
- Pyrazinamide → hyperuricemia (gout), hepatotoxicity.
- Ethambutol → "E = Eye": optic neuritis (↓ red-green color vision, ↓ acuity).
All except ethambutol are hepatotoxic.
- Active, drug-susceptible TB: RIPE ×2 months (intensive) → rifampin + isoniazid ×4 months (continuation) = 6 months total, given under DOT. *(2022 alternative: a 4-month rifapentine–moxifloxacin regimen.)*
- Latent TB (preferred rifamycin-based short courses): 3HP (weekly isoniazid + rifapentine ×12), 4R (rifampin daily ×4 mo), or 3HR (isoniazid + rifampin ×3 mo). INH ×6–9 mo is an older alternative.
- Before therapy: baseline LFTs; visual acuity + color testing for ethambutol; add pyridoxine with INH.
- Monitor: symptoms + LFTs; repeat sputum cultures to confirm conversion.
- Public health: airborne isolation until clinical improvement / smear conversion; mandatory reporting + contact tracing.
- MDR-TB = resistant to ≥ isoniazid + rifampin → regimens with newer agents (e.g., bedaquiline); specialist referral.
A 52-year-old woman with rheumatoid arthritis is about to start infliximab (a TNF-α inhibitor). She is asymptomatic with a normal exam.
Next best step: screen for latent TB (IGRA or TST) + baseline CXR before starting the biologic. Why: TNF-α maintains granuloma integrity, so anti-TNF therapy can reactivate latent TB. If LTBI is confirmed (positive test, normal CXR, no symptoms), treat latent TB first (e.g., 3HP or 4R).
Toxicity next-steps to know:
- Patient on INH with tingling/numb feet → B6 deficiency neuropathy → give pyridoxine.
- New ↓ color vision / acuity on therapy → stop ethambutol (optic neuritis).
- Orange tears/urine on therapy → rifampin, reassure (harmless).
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