What is the approach to diagnosing and treating Tuberculosis (TB)?

Diagnosis of Tuberculosis

For any patient with suspected TB, immediately obtain three sputum specimens on different days for AFB smear microscopy and mycobacterial culture (both liquid and solid media), as culture remains the gold standard for diagnosis. 1, 2

Clinical Suspicion and Initial Evaluation

Consider TB in any patient with cough lasting ≥3 weeks, particularly when accompanied by:

• Evening fever and night sweats
• Weight loss and anorexia
• Hemoptysis
• Radiographic findings suggestive of TB (apical cavitary lesions, infiltrates) 1, 2

The threshold for suspicion should be lower in high-prevalence areas and high-risk populations (HIV-infected, immunosuppressed, foreign-born from endemic countries, homeless, incarcerated). 1

Diagnostic Algorithm for Pulmonary TB

Step 1: Sputum Collection and Microscopy

• Collect three sputum specimens on different days (optimal volume 5-10 mL, minimum 3 mL) to maximize sensitivity 1, 2
• Perform AFB smear microscopy using concentrated specimens with fluorescence microscopy (preferred method) 1
• Important caveat: Negative AFB smears do NOT exclude TB—false negatives are common due to low bacillary load, temporal variation in organism shedding, or processing errors 1
• Positive AFB smears provide presumptive evidence but do NOT confirm TB, as nontuberculous mycobacteria can cause false positives 1

Step 2: Mycobacterial Culture

• Perform both liquid and solid culture on all specimens—liquid culture is faster (results in 1-3 weeks vs 3-8 weeks for solid media) 1
• Culture is the gold standard and essential for species identification and drug susceptibility testing 1
• Isolates must be identified according to standard guidelines and undergo susceptibility testing for first-line drugs 1

Step 3: Nucleic Acid Amplification Testing (NAAT)

• Perform NAAT on the initial respiratory specimen in patients with intermediate-to-high suspicion for TB 1
• In AFB smear-positive patients: positive NAAT confirms TB; negative NAAT suggests nontuberculous mycobacteria 1
• In AFB smear-negative patients: positive NAAT provides presumptive evidence of TB, but negative NAAT cannot exclude disease 1
• Approved tests include Cepheid Xpert MTB/RIF and Hologic Amplified MTD 1

Step 4: Rapid Molecular Drug Susceptibility Testing

Perform rapid molecular testing for rifampin resistance (with or without isoniazid) if the patient meets ANY of these criteria: 1

• Previous TB treatment
• Born in or lived ≥1 year in countries with TB incidence ≥20 per 100,000 or MDR-TB prevalence ≥2%
• Contact of known MDR-TB patient
• HIV infection

Radiographic Evaluation

• Chest radiography is essential but cannot establish TB diagnosis alone 1, 3
• Classic findings include apical cavitary lesions, infiltrates, lymphadenopathy, and pleural effusions 2, 4
• CT scanning is indicated when: 4
  • Chest X-ray is normal but clinical suspicion remains high
  • Patient is immunocompromised (may have atypical presentations)
  • Differentiation from other diseases is needed

Culture-Negative Pulmonary TB

When clinical and radiographic findings suggest TB but cultures remain negative (occurs in ~17% of US cases): 1

1. Ensure adequate specimen collection: minimum three induced sputum samples; consider bronchoscopy with bronchoalveolar lavage and biopsy 1
2. Carefully exclude alternative diagnoses through appropriate testing 1
3. Initiate empiric four-drug therapy (isoniazid, rifampin, pyrazinamide, ethambutol) even with negative smears 1
4. Reassess at 2 months: if clinical/radiographic improvement occurs without alternative diagnosis, continue treatment 1
5. Shorten continuation phase to 2 months (total 4 months of isoniazid/rifampin) if cultures remain negative and clinical response is good 1

Testing for Latent TB Infection (LTBI)

Use tuberculin skin test (TST) and/or interferon-gamma release assay (IGRA) to diagnose LTBI: 1, 5

Dual Testing Strategy (Recommended in Medium/High TB Prevalence Settings)

• Perform both TST and IGRA in patients with TB risk factors and immunosuppression to improve diagnostic yield 1
• IGRAs (QuantiFERON-TB Gold, T-SPOT) have advantages: no cross-reactivity with BCG vaccination (except M. kansasii, M. marinum, M. szulgai), and higher specificity in BCG-vaccinated populations 1
• Critical limitation: Both TST and IGRA have reduced sensitivity in immunosuppressed patients 1

LTBI Evaluation Protocol

1. Obtain clinical history (TB exposure, risk factors, symptoms) 1, 5
2. Perform TST and/or IGRA 1, 5
3. If positive: obtain chest X-ray immediately to exclude active disease 5
4. Assess for TB symptoms (cough, fever, weight loss, night sweats) 5
5. Collect sputum for testing ONLY if chest X-ray is abnormal or symptoms present 5

Special Populations

High-Priority Contacts Requiring Immediate Evaluation

• Children <5 years old
• HIV-infected individuals
• Immunocompromised patients
• These groups require TST/IGRA at initial evaluation, chest X-ray regardless of test results, and repeat testing 8-10 weeks post-exposure if initial test negative 5

Pregnant Women

• Avoid streptomycin (causes congenital deafness) and pyrazinamide (inadequate safety data) 6
• Initial regimen: isoniazid, rifampin, and ethambutol (unless isoniazid resistance <4%) 6

Common Pitfalls to Avoid

1. Do not rely on single negative sputum specimen—always collect three samples on different days 1, 2
2. Do not exclude TB based on negative AFB smears alone—proceed with culture and NAAT 1
3. Do not delay treatment in high-suspicion cases while awaiting culture results 1
4. Do not use TST/IGRA to diagnose active TB—these tests only indicate infection, not active disease 1, 2
5. Do not assume non-infectiousness after starting treatment—patients remain potentially infectious until three consecutive negative sputum smears on different days with clinical improvement 1