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Relapse and Reinfection of Tuberculosis

Introduction

1. Relapse — reactivation of the same strain of Mycobacterium tuberculosis that caused the original infection (endogenous reactivation of persisting bacilli)
2. Reinfection — acquisition of a new, different strain of M. tuberculosis (exogenous reinfection)

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Definitions

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How to Distinguish Relapse from Reinfection

• Relapse: Both episodes show identical or highly similar M. tuberculosis DNA fingerprint (e.g., MIRU-VNTR, spoligotyping, or whole-genome sequencing [WGS])
• Reinfection: The second episode shows a different strain genotype

• CRISPR/Spoligotyping — widely used, targets direct repeat loci
• MIRU-VNTR — mycobacterial interspersed repetitive units; highly discriminatory
• Whole-genome sequencing (WGS) — highest precision; resolves transmission clusters and can determine directionality of transmission at the single-nucleotide polymorphism level

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Epidemiology

• In patients with drug-susceptible TB receiving a standard 6-month rifamycin-based DOT regimen:
  • Treatment failure rate: < 1%
  • Relapse rate: approximately 4%
• In low-burden settings (where reinfection is uncommon), relapse and recurrence rates are even lower
• In high-burden settings (e.g., Sub-Saharan Africa, Southeast Asia), reinfection is a major contributor to recurrence, particularly in HIV-positive individuals
• HIV infection increases reinfection risk 4.65-fold (RR 4.65; 95% CI 1.71–12.65) — Vega et al., BMJ Open Respir Res 2024 [PMID: 38479821]

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Risk Factors

Risk Factors for Relapse

Risk Factors for Reinfection

• High TB burden environment — repeated exposure to infectious cases
• HIV infection — dramatically increases susceptibility to new strains (RR 4.65)
• Immunosuppression — prevents immune control of new inoculum
• Incomplete treatment — may not achieve sterilizing immunity against new strains

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Pathogenesis

Relapse (Endogenous Reactivation)

1. Bacterial persisters (non-replicating bacilli resistant to killing) survive beyond the treatment course
2. Host immunity wanes (e.g., HIV progression, new immunosuppression)
3. Treatment was inadequate in duration, dosage, or drug susceptibility

Reinfection (Exogenous Reinfection)

• High-transmission settings (crowded housing, prisons, healthcare settings)
• Persons with HIV (impaired mucosal and cellular immunity)
• Persons with repeated occupational exposure

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Clinical Features of Recurrent TB

• Symptoms are similar to primary TB: productive cough, hemoptysis, fever, night sweats, weight loss, fatigue
• Recurrent TB due to MDR strains may present with a more refractory course
• Paradoxical reactions must be distinguished from true relapse — they represent inflammatory flares during treatment, not bacteriological failure
• Smear-positive sputum with no growth on culture may represent dead/non-viable bacilli (not true relapse)

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Investigations

1. Sputum AFB smear and culture (most critical) — confirms recurrence
2. Drug susceptibility testing (DST) — first- and second-line drugs; at a reference laboratory for patients with treatment failure
3. Molecular genotyping (MIRU-VNTR, WGS) — to distinguish relapse from reinfection
4. Chest X-ray — assess cavitation and extent of disease
5. HIV serology — essential in all patients with recurrent TB
6. Blood glucose — rule out diabetes
7. Therapeutic drug monitoring (TDM) — in cases of suspected malabsorption or poor drug exposure
8. Sputum culture at 2 months — important prognostic indicator; positive at 2 months is a risk factor for relapse

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Management of Recurrent TB

General Principles

1. Identify and address cause of recurrence before starting treatment
2. Never add a single drug to a failing regimen — this amplifies resistance
3. Add 2–3 new drugs with inferred susceptibility
4. Consult a specialist center for drug-resistant cases
5. Ensure strict DOT (directly observed therapy)

Treatment Approach Based on Cause

Prolonging Treatment to Prevent Relapse

• Patients with cavitation + positive 2-month culture → 9-month total regimen (7-month continuation phase)
• Prolonging once-weekly INH/rifapentine continuation phase from 4 to 7 months decreased relapse rates in high-risk groups
• Additional indications to extend treatment: >10% underweight, poor weight gain, smoker, diabetes, HIV, extensive disease, poor adherence

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Prevention of Recurrence

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Summary Table

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Recent Evidence (2024 Meta-Analysis)

• MDR-TB in the previous episode: RR 3.49 for undifferentiated recurrence
• Fixed-dose combination drugs: RR 2.29 for recurrence (subtherapeutic levels under field conditions)
• HIV infection: RR 4.65 specifically for reinfection
• Poor treatment adherence: RR 3.3 for recurrence (though evidence certainty was weak)
• Key conclusion: Preventing MDR-TB, ensuring treatment retention, and integrated HIV care are the most important interventions to reduce recurrence

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Key Points for MD Exam

1. Relapse = same strain reactivation; Reinfection = new strain — distinguished only by molecular genotyping
2. Genotyping methods: spoligotyping, MIRU-VNTR, WGS (most precise)
3. Failure rate <1%, relapse rate ~4% with standard 6-month DOT regimen
4. Highest relapse risk: cavitation + positive 2-month culture (≈20% relapse rate)
5. Never add a single drug to a failing regimen — amplifies resistance
6. Treatment extension: cavitation + positive 2-month culture → extend to 9 months total
7. HIV is the dominant risk factor for reinfection (RR 4.65)
8. MDR-TB is the dominant risk factor for recurrence (RR 3.49)
9. DOT remains the standard of care; <90% adherence → HR 5.9 for poor outcomes
10. Paradoxical reaction ≠ relapse — must be excluded before diagnosing treatment failure

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