Key Facts

Latent TB infection (LTBI) represents a state of persistent immune response to M. tuberculosis antigens without clinical evidence of active disease. Identifying and treating LTBI is a key public health strategy to prevent future active TB cases.

Epidemiology

• Estimated 1/4 of the world's population has LTBI (WHO)
• UK LTBI prevalence: estimated ~500,000–800,000 people
• ~80% of UK active TB cases arise from reactivation of LTBI
• New entrant screening programme identifies thousands of LTBI cases annually
• Risk of reactivation: 5–10% lifetime (immunocompetent); 5–15% per year (HIV+)

Aetiology

• Prior infection with M. tuberculosis that has been contained by the immune system
• High-risk groups for LTBI: immigrants from high-incidence countries, contacts of active TB cases, healthcare workers, prisoners, homeless, IVDU
• High-risk for reactivation: HIV, anti-TNF therapy, other immunosuppression (transplant, chemotherapy), diabetes, CKD, malnutrition, silicosis

Pathophysiology

• After primary infection, granuloma formation contains M. tuberculosis
• Bacilli remain viable but dormant within granulomas (caseous necrosis surrounded by macrophages and T-cells)
• Memory T-cells maintain immune surveillance (basis of IGRA and Mantoux tests)
• Immunosuppression → granuloma breakdown → reactivation → active TB
• Reactivation typically occurs in lung apices (highest oxygen tension) but can affect any organ

Typical Presentation

• Asymptomatic — by definition, no clinical features
• Identified through screening programmes
• Positive IGRA or Mantoux without symptoms or CXR abnormality

Screening Contexts

• New entrant screening from high-incidence countries
• Contact tracing of active TB case
• Pre-immunosuppression screening (before anti-TNF, transplant)
• Occupational health screening (healthcare workers)
• HIV diagnosis

Red Flags (suggesting active rather than latent TB)

• Any respiratory symptoms (cough, haemoptysis)
• Systemic symptoms (fever, night sweats, weight loss)
• Abnormal CXR
• Lymphadenopathy
• These require investigation for active TB before treating as LTBI

Screening Tests

• IGRA: QuantiFERON-TB Gold Plus or T-SPOT.TB

  • Measures interferon-gamma release by T-cells in response to TB-specific antigens (ESAT-6, CFP-10)
  • Not affected by BCG vaccination (unlike Mantoux)
  • Sensitivity ~90%, specificity ~95%
  • Single blood test, result in 24–48 hours

• Mantoux test (TST): intradermal injection of 2TU PPD

  • Read at 48–72 hours
  • Positive: ≥5mm (immunocompromised, close contacts); ≥15mm (BCG-vaccinated)
  • Affected by BCG, NTM, immunosuppression

To Exclude Active TB

• CXR: must be normal for LTBI diagnosis
• Symptom enquiry: cough, fever, night sweats, weight loss
• Sputum: only if symptoms or CXR abnormal
• HIV test: recommended for all LTBI patients

Before Treatment

• LFTs: baseline (hepatotoxic drugs)
• Hepatitis B/C serology: increased hepatotoxicity risk
• eGFR: dose adjustment if impaired

Non-pharmacological

• Patient education: importance of treatment completion, symptoms of active TB, drug side effects
• Risk-benefit discussion: individualised decision based on reactivation risk vs treatment toxicity
• Contact tracing: if identified through contact screening, ensure index case is managed

Pharmacological

NICE NG33 recommended regimens:

1. 3HR (preferred): isoniazid 300mg OD + rifampicin 450/600mg OD for 3 months + pyridoxine 10mg OD
2. 6H: isoniazid 300mg OD for 6 months + pyridoxine 10mg OD (if rifampicin interactions problematic)
3. 3HP (weekly rifapentine + isoniazid): increasingly used but not yet standard UK practice

Before anti-TNF therapy:

• Screen with IGRA + CXR
• If LTBI: complete at least 2 months of treatment before starting anti-TNF
• If unable to treat: monitor closely for active TB

Monitoring:

• LFTs at baseline, 2 weeks, then monthly
• Symptom review at each visit
• Stop treatment and investigate if: hepatitis symptoms, transaminases >3× ULN with symptoms or >5× ULN without symptoms

Drug interactions:

• Rifampicin: potent enzyme inducer — affects warfarin, OCP, immunosuppressants, antiretrovirals
• Isoniazid: inhibits CYP2C19, CYP3A4 — interacts with phenytoin, carbamazepine

BCG Vaccination

• Neonates: offered in high-incidence areas (≥40/100,000) or with family links to high-incidence countries
• Previously unvaccinated contacts of active TB: BCG if Mantoux/IGRA negative and aged <35
• Not given if: HIV+ (unless CD4 >200 and on ART), immunosuppressed, previous BCG, positive Mantoux/IGRA

Referral Criteria

• TB specialist: all LTBI for treatment decision and monitoring
• Specialist advice: HIV co-infection, drug interactions (transplant, rheumatology patients on biologics)
• GP: follow-up monitoring for uncomplicated cases on isoniazid monotherapy

• LTBI treatment reduces reactivation risk by 60–90%
• 3HR regimen: completion rates ~80% (better than 6H due to shorter duration)
• 6H regimen: completion rates ~60%
• Untreated LTBI: 5–10% lifetime reactivation risk (immunocompetent)
• HIV co-infection without treatment: 5–15% per year reactivation risk
• BCG: 70–80% effective against severe childhood TB (miliary, meningitis)
• After completed LTBI treatment: reactivation risk <1%
• Drug-induced hepatitis: <1% with isoniazid at standard dose (higher in >35 years, alcohol use, hepatitis)

IGRA vs Mantoux Comparison

LTBI Treatment Regimens

UK LTBI Screening Programme