What is the diagnostic and treatment algorithm for a patient suspected of having either active tuberculosis (TB) or latent TB infection?

Algorithm for Distinguishing Active TB from Latent TB Infection

The critical first step is to rule out active TB disease before considering latent TB infection, using a combination of symptom screening, chest radiography, and microbiological testing—never rely on TST or IGRA alone to make this distinction, as these tests cannot differentiate between active disease and latent infection. 1, 2, 3

Step 1: Clinical Symptom Assessment

Screen all patients for TB symptoms before any testing:

• Active TB symptoms include: cough ≥2-3 weeks, hemoptysis, fever, night sweats, weight loss, chest pain, shortness of breath, and fatigue 1, 2, 4, 3
• Latent TB infection: completely asymptomatic with no signs or symptoms of disease 3
• Critical pitfall: The presence of any TB symptom mandates evaluation for active disease, not just LTBI testing 1

Step 2: Chest Radiography

Obtain chest X-ray on all patients being evaluated for TB:

• Active TB radiographic findings: upper lobe or superior-segment lower lobe fibrocavitary disease, infiltrates, cavitation, tree-in-bud nodules, hilar/mediastinal lymphadenopathy, or pleural effusions 1, 2, 3
• Latent TB infection: normal chest radiography 3
• If immunocompromised (especially HIV or low CD4 count): obtain CT scan even if chest X-ray appears normal, as subtle parenchymal disease or lymphadenopathy may be missed 1

Step 3: Microbiological Testing (If Active TB Suspected)

When symptoms or radiographic abnormalities are present:

• Collect three sputum specimens on different days for AFB smear microscopy and mycobacterial culture 2, 4
• Perform nucleic acid amplification testing (NAAT) on at least one respiratory specimen for rapid diagnosis within 1-2 days 2
• Interpretation algorithm based on results: 2
  • AFB smear positive + NAAT positive = Presume active TB, begin four-drug treatment immediately (positive predictive value >95%)
  • AFB smear negative + NAAT positive = Consider testing additional specimen; if ≥2 specimens NAAT-positive, presume TB pending culture
  • AFB smear positive + NAAT negative = Test for PCR inhibitors; if no inhibitors and repeat specimen remains smear-positive but NAAT-negative, presume nontuberculous mycobacterial infection
• Mycobacterial culture remains the gold standard for definitive diagnosis and drug susceptibility testing 2, 4, 3

Critical caveat: Never exclude TB based on negative AFB smears alone—culture is mandatory 2

Step 4: TST or IGRA Testing (Only After Ruling Out Active Disease)

Use TST or IGRA only to diagnose latent TB infection after active disease is excluded:

• Either TST or IGRA can be used in high-income countries with TB incidence <100 per 100,000 1
• IGRA advantages: no cross-reactivity with BCG vaccination, higher specificity in BCG-vaccinated populations 2
• TST interpretation: 1
  • ≥5 mm induration: positive in HIV-infected, recent TB contacts, or radiographic evidence of prior TB
  • ≥10 mm induration: positive in recent immigrants from high-prevalence countries, injection drug users, healthcare workers, or patients with diabetes, chronic renal failure, or immunosuppression
  • ≥15 mm induration: positive in low-risk individuals

Both tests predict risk of progression to active TB, with similar predictive utility 1

Step 5: Treatment Decision Algorithm

If Active TB Disease Confirmed:

• Initial phase (2 months): isoniazid, rifampin, pyrazinamide, and ethambutol daily 4, 5, 6, 7
• Continuation phase (4 months): isoniazid and rifampin 4, 7, 8
• Maintain respiratory isolation until three consecutive negative sputum smears on different days 4, 3
• Never use monotherapy in any phase of active TB treatment 5

If Latent TB Infection Confirmed (Positive TST/IGRA + Normal CXR + No Symptoms):

Preferred treatment regimens: 1, 7

• 3 months of weekly rifapentine plus isoniazid (12 doses total, directly observed therapy) 5
• 4 months of daily rifampin alone 1
• 6-9 months of daily isoniazid 1

High-priority populations requiring systematic LTBI testing and treatment: 1

• HIV-infected individuals
• Close contacts of active pulmonary TB cases
• Patients initiating anti-TNF treatment
• Patients on dialysis or preparing for transplantation
• Patients with silicosis

Common Pitfalls to Avoid

• Never use TST or IGRA to diagnose active TB disease—these tests cannot distinguish active from latent infection 2, 3
• Never delay treatment in high-suspicion cases while awaiting culture results 2
• Never assume non-infectiousness immediately after starting treatment—wait for three negative sputum smears 2, 3
• Never rely on single negative sputum specimen to exclude TB 2
• Never use rifapentine once weekly in HIV-infected patients with active TB due to higher failure/relapse rates with rifampin-resistant organisms 5
• Always rule out active TB before treating LTBI—active disease requires multi-drug therapy, not single-agent LTBI regimens 5