When should a relapse of pulmonary tuberculosis (PTB) be considered in a patient with a history of previous TB treatment, HIV co-infection, or other immunocompromising conditions?

When to Consider PTB Relapse

Consider PTB relapse when a patient who previously achieved culture-negative status during treatment develops recurrent symptoms (cough, fever, night sweats, weight loss, hemoptysis) or radiographic deterioration after completing therapy, with most relapses occurring within 6-12 months post-treatment. 1

Clinical Definition of Relapse

Relapse is defined as a patient who became and remained culture-negative while receiving antituberculosis drugs but subsequently becomes culture-positive again or experiences clinical or radiographic deterioration consistent with active tuberculosis after completing therapy. 1

Timing of Relapse Occurrence

• Most relapses (77%) occur within the first 6 months after treatment completion, with the majority happening within 6-12 months. 2, 3
• The median time for recurrence is 18 months from treatment completion. 3
• Relapses occurring beyond 12 months are less common but still possible, particularly in high TB burden settings where reinfection becomes more likely than true relapse. 2, 3

High-Risk Patients Most Likely to Relapse

Patients with extensive tuberculosis whose sputum cultures remain positive after 2 months of chemotherapy are at highest risk for relapse. 1

Specific Risk Stratification:

• Both cavitation on initial chest radiograph AND positive culture at 2 months: 18-21% relapse risk - these patients require extended treatment to 9 months total duration. 2, 4, 5
• Either cavitation OR 2-month positive culture alone: 5-6% relapse risk - consider individual treatment extension. 2, 5
• Neither risk factor present: 2% relapse risk - standard 6-month treatment is sufficient. 2

Additional Risk Factors:

• Patients who received self-administered therapy (not DOT) have substantially higher relapse risk with drug-resistant organisms. 1
• HIV-infected patients not receiving antiretroviral therapy during TB treatment have increased relapse risk and should receive 9 months total treatment. 1, 6
• Irregular treatment compliance increases relapse risk significantly. 6
• Older age (≥30 years) in HIV-infected patients is associated with increased relapse risk. 6

Clinical Presentation Triggering Relapse Evaluation

Actively pursue relapse evaluation when patients present with:

• Persistent cough lasting >2-3 weeks 2
• Fever, particularly with night sweats 2
• Unexplained weight loss 2
• Hemoptysis 2
• Radiographic deterioration on chest imaging 1

Critical Diagnostic Approach When Relapse is Suspected

Obtain at least three sputum specimens for AFB smear, mycobacterial culture, and drug susceptibility testing BEFORE initiating any treatment modifications. 2, 7, 8

• Perform rapid molecular testing (Xpert MTB/RIF) immediately to detect rifampicin resistance. 7, 8
• Never modify treatment without obtaining specimens first, as this eliminates the opportunity to identify resistance patterns. 2, 7, 8
• Send isolates to a reference laboratory for comprehensive first-line and second-line drug susceptibility testing. 7, 8

Distinguishing True Relapse from Reinfection

• In low TB burden settings, recurrences are mainly caused by relapse (85% of cases). 3
• In high TB burden settings, relapses comprise only 56% of recurrences, with reinfection accounting for the remainder. 3
• Early recurrences (<12 months) are mainly relapses, while late recurrences (>24 months) are mainly reinfections. 3
• Relapse occurs earlier at a median of 12 months versus reinfection at 24 months. 3

Drug Resistance Patterns in Relapse

For patients who completed prior treatment under DOT with rifamycin-containing regimens, nearly all relapses occur with drug-susceptible organisms. 1, 7

However, for patients who received self-administered therapy or non-rifamycin regimens, the risk of acquired drug resistance is substantial. 1, 7

• Emergence of resistance to one or more first-line anti-TB agents occurs in approximately 9.5% of recurrence cases. 3

Post-Treatment Surveillance Strategy

For patients without risk factors for relapse, no routine follow-up visits are required after treatment completion. 2

• Patients should receive clear instructions to return immediately if they develop symptoms suggestive of relapse. 2
• Do not rely on routine annual chest radiographs or sputum checks in asymptomatic patients, as this approach has poor yield and is not cost-effective. 2, 9
• Only one-fourth of relapse cases are detected during routine annual checkups; the remaining three-fourths present symptomatically. 9

Common Pitfalls to Avoid

• Do not assume all recurrences are true relapses in high-incidence areas - consider exogenous reinfection and obtain genotyping if available. 2, 7
• Do not delay obtaining specimens for culture and susceptibility testing when relapse is suspected, even if starting empiric treatment. 2, 7
• Do not use intermittent (once or twice weekly) regimens for retreatment, especially in HIV-infected patients, due to high failure and resistance rates. 1
• Exercise caution when interpreting PCR results, as false-positive detection of M. tuberculosis DNA can occur, and PCR cannot distinguish between viable and dead organisms. 7