What is the appropriate diagnostic work‑up and initial management for a 25‑year‑old man with a history of childhood primary tuberculosis treated with isoniazid, rifampin, pyrazinamide, and ethambutol for one year, a positive Mantoux test, normal chest CT, and recent 9 kg unintentional weight loss, severe fatigue, exertional chest tightness, tachycardia, diaphoresis, and hypertension?

Diagnostic Work-Up and Management

This patient requires urgent evaluation for extrapulmonary tuberculosis and alternative diagnoses, not routine TB treatment, given the discordance between systemic symptoms and normal chest imaging.

The clinical picture—significant unintentional weight loss (9 kg), severe fatigue, exertional symptoms with tachycardia, hypertension, and diaphoresis in a young man with a positive Mantoux but normal chest CT—strongly suggests either extrapulmonary TB or a non-tuberculous process such as hyperthyroidism, pheochromocytoma, or other systemic disease.

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Immediate Diagnostic Priorities

Rule Out Active Extrapulmonary TB

• Obtain three sputum samples for AFB smear and culture even with normal chest CT, as culture-negative pulmonary TB can present with systemic symptoms 1
• Assess for lymph node, abdominal, or disseminated TB through physical examination focusing on peripheral lymphadenopathy, hepatosplenomegaly, and abdominal masses 1
• Consider abdominal CT or ultrasound to evaluate for intra-abdominal lymphadenopathy or organ involvement, particularly given the weight loss 1
• Check HIV status immediately as HIV-infected individuals have higher rates of extrapulmonary TB and atypical presentations 1

Exclude Non-TB Systemic Diseases

• Thyroid function tests (TSH, free T4) to rule out hyperthyroidism, which classically presents with weight loss, tachycardia, heat intolerance/sweating, and fatigue
• 24-hour urine metanephrines or plasma metanephrines to exclude pheochromocytoma, which causes episodic hypertension, tachycardia, diaphoresis, and chest tightness
• Complete blood count, comprehensive metabolic panel, and inflammatory markers (ESR, CRP) to assess for systemic inflammation or other pathology
• Echocardiogram to evaluate cardiac function given exertional chest tightness and tachycardia

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Critical Interpretation of Mantoux Positivity

A positive Mantoux test in this patient likely represents latent TB infection (LTBI) from his childhood primary complex, NOT active disease, given:

• Normal chest CT findings 1
• Previous adequate treatment with HRZE for one year (though standard duration is 6-9 months) 1, 2
• Absence of pulmonary symptoms or radiographic changes 1

The Mantoux test cannot distinguish between LTBI and active TB, and in someone with documented prior TB treatment, it is expected to remain positive indefinitely 1

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Management Algorithm Based on Diagnostic Findings

If Sputum Cultures Are Negative AND No Extrapulmonary TB Found

Do NOT initiate multi-drug TB therapy. Instead:

1. Pursue alternative diagnoses aggressively (thyroid disease, pheochromocytoma, cardiac disease, malignancy)
2. If all workup is negative and symptoms persist at 2-3 months, consider three treatment options for presumed LTBI 1:
   • Isoniazid for 9 months
   • Rifampin with or without isoniazid for 4 months
   • Rifampin and pyrazinamide for 2 months (only if adherence can be closely monitored)

If Active TB Is Confirmed (Positive Cultures or Biopsy)

Initiate standard four-drug therapy immediately 1, 2:

• Isoniazid, rifampin, pyrazinamide, and ethambutol daily for 2 months, followed by
• Isoniazid and rifampin for 4 months (total 6 months for pulmonary TB)

For extrapulmonary TB (excluding CNS, bone/joint, or miliary disease):

• Use the same 6-month regimen as pulmonary TB 2, 3
• For CNS, bone/joint, or miliary TB in adults: extend continuation phase to 7-10 months (total 9-12 months) 1

If Drug Resistance Is Suspected

Given his history of previous TB treatment, there is increased risk of drug resistance 1. If cultures grow TB:

• Wait for drug susceptibility testing results before modifying therapy 1
• If isoniazid-resistant but rifampin-susceptible: continue all four drugs for 6 months 4
• If rifampin-resistant or MDR-TB: consult TB specialist immediately and treat for 18-24 months with second-line agents 1, 2

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Common Pitfalls to Avoid

1. Do not assume positive Mantoux equals active TB—this patient's test likely reflects his childhood infection, not current disease 1
2. Do not start empiric TB treatment without microbiological or histological confirmation when chest imaging is normal and symptoms are non-specific 1
3. Do not overlook life-threatening alternative diagnoses like pheochromocytoma or thyrotoxicosis that can mimic TB systemically
4. Do not use the 2-month rifampin/pyrazinamide regimen for LTBI except in patients unlikely to complete longer therapy, due to hepatotoxicity risk 1

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Monitoring During Workup

• Weekly clinical assessment until diagnosis is established
• Repeat weight measurement at each visit
• Serial vital signs to track tachycardia and hypertension trends
• If TB treatment is initiated: baseline liver function tests, complete blood count, creatinine, and visual acuity (for ethambutol) 1, 5
• Follow-up sputum cultures at 2 months if TB treatment is started, as positive cultures at this point indicate need for extended therapy 1