How tuberculosis is tested on Step 1

Expect a patient with cough, night sweats, weight loss, and an apical cavity, a positive screening test in an asymptomatic health worker, or a drug toxicity during treatment.

workspace_premium Containment depends on Th1 immunity

TB is controlled by IFN-γ–activated macrophages in granulomas. Anything that weakens that axis — HIV, TNF-α inhibitors, steroids, IL-12 or IFN-γ receptor defects — allows reactivation or spread.

Pathogenesis

Inhaled bacilli are engulfed by alveolar macrophages but block phagolysosome fusion and multiply.

InhaledbacilliAlveolarmacrophagesIL-12MacrophagesignalTh1 cellsSecrete IFN-γActivatedmacrophagesEpithelioid,giant cellsCaseatinggranulomaTNF-αmaintains it
Granuloma formation. Screen for latent TB before TNF-α inhibitors (infliximab, adalimumab), which dissolve granulomas.
Primary TBFirst exposureSubpleural Ghon focus, mid-lungGhon complex: focus + hilar nodeUsually contained → latentProgressive primary in children, HIVSecondary (reactivation) TBReactivation of latent infectionApical lesions (high O₂ tension)Caseation and cavitationCough, hemoptysis, night sweats, weightlossContagiousvs
Primary vs secondary TB. Hematogenous spread produces miliary TB and extrapulmonary disease (Pott disease of the spine, meningitis, adrenal).

Testing for TB

Screening tests detect immune memory; they cannot separate latent from active infection.

TestPrincipleNotes
Tuberculin skin test (PPD)Type IV hypersensitivity induration at 48–72 hFalse positive after BCG vaccine; false negative in immunosuppression, sarcoid
Interferon-γ release assay (IGRA)T cells release IFN-γ to TB-specific antigensNot affected by BCG; single visit
Sputum AFB smear, culture, NAATDetects organismCulture is the gold standard (weeks); NAAT gives rapid rifampin resistance
Chest x-rayExcludes active diseaseRequired after any positive screening test

PPD positivity thresholds: ≥ 5 mm (HIV, close contacts, immunosuppressed), ≥ 10 mm (high-risk settings, recent immigrants, health workers), ≥ 15 mm (no risk factors).

Treatment

Active TB needs multiple drugs to prevent resistance; latent TB needs a shorter regimen to prevent reactivation.

RIPE therapyRifampinDNA-dependent RNApolymeraseIsoniazidMycolic acidsynthesis (via KatG)PyrazinamideUnclear; acidic pHEthambutolArabinosyltransferase
RIPE. Standard regimen: 2 months of all four, then 4 months of rifampin and isoniazid.
DrugKey toxicityPrevention or note
IsoniazidPeripheral neuropathy, hepatitis, drug-induced lupus, sideroblastic anemiaPyridoxine (B6); slow acetylators at higher risk
RifampinOrange-red body fluids, hepatitis, strong CYP inducerLowers levels of warfarin, contraceptives, HIV drugs
PyrazinamideHyperuricemia, gout, hepatitisMonitor uric acid
EthambutolOptic neuritis (red-green color blindness)Check visual acuity and color vision

Latent TB: 3 months of weekly isoniazid + rifapentine, 4 months of rifampin, or 3 months of isoniazid + rifampin.

Clinical application

Drug side effects during TB therapy are high yield.

functions Worked example — tingling feet on therapy

A 44-year-old with alcohol use disorder and malnutrition is two months into RIPE therapy for cavitary TB. She reports burning and tingling in both feet. Which drug is responsible, and how could it have been prevented?

  1. Symmetric distal sensory neuropathy during TB therapy points to isoniazid.
  2. Isoniazid forms a complex with pyridoxine, depleting vitamin B6, which is needed for neurotransmitter synthesis.
  3. Malnutrition and alcohol use raise the risk.

Answer. Isoniazid-induced pyridoxine deficiency. Give pyridoxine (vitamin B6) with isoniazid, especially in high-risk patients.