What other infections need to be ruled out in patients with suspected latent tuberculosis (TB) infection?

Infections to Rule Out in Suspected Latent TB

The primary infection that must be ruled out is active tuberculosis disease itself, which requires chest radiography and sputum examination for acid-fast bacilli if pulmonary symptoms or radiographic abnormalities are present. 1

Active TB Disease Exclusion (Primary Priority)

Active TB must always be excluded before diagnosing or treating latent TB infection. This is the most critical differential diagnosis because:

• Patients with active TB require multi-drug therapy, not single-agent LTBI treatment 1
• Clinical indicators of active disease include: persistent cough ≥3 weeks, hemoptysis, night sweats, weight loss, fever, or anorexia 1
• Chest radiography should be performed on all patients with positive TST or IGRA to identify infiltrates, cavitation, or other findings suggestive of active disease 1
• If chest X-ray is abnormal or symptoms are present, sputum specimens must be collected for AFB smear and culture 1

Important caveat: Calcified granulomas alone represent healed primary TB and do not indicate active disease in asymptomatic patients 2. However, fibronodular infiltrations suggest prior TB requiring heightened concern 2.

Viral Hepatitis Screening

Before initiating LTBI treatment with hepatotoxic medications (isoniazid, rifampin), viral hepatitis must be assessed:

• Hepatitis B (HBV) and Hepatitis C (HCV) serology should be checked prior to starting anti-TNF therapy or immunosuppressive treatment 1
• This is particularly important because LTBI treatment regimens can cause hepatotoxicity, and underlying liver disease increases this risk 1, 2
• Baseline liver function tests are indicated for patients with history of liver disease 2

HIV Infection

HIV testing should be performed as part of the infectious disease workup in patients with suspected LTBI:

• HIV-positive individuals have dramatically increased risk of TB reactivation 1
• HIV coinfection affects treatment thresholds (TST ≥5mm is considered positive) 1, 2
• HIV status influences treatment regimen selection and monitoring intensity 1

Parasitic Infections (Geographic Risk-Based)

For patients with travel history or residence in endemic areas:

• Strongyloides stercoralis serology and eosinophil count should be checked before starting immunosuppressive therapy 1
• This is critical because immunosuppression can cause Strongyloides hyperinfection syndrome, which is potentially fatal 1
• Consider screening for other parasitic infections based on specific geographic exposure 1

Fungal Infections (Context-Dependent)

In immunocompromised patients or those from endemic regions, consider:

• Histoplasma capsulatum - particularly if chest radiograph shows scarring that could be confused with TB 1
• Endemic fungal infections may present similarly to TB with pulmonary infiltrates 1
• Screening is especially relevant for patients who will receive anti-TNF or other biologic therapy 1

Varicella Zoster Virus (VZV)

• VZV serology should be checked in patients without clear history of chickenpox or prior vaccination 1
• This is part of the standard pre-immunosuppression screening panel 1
• Relevant because immunosuppressive therapy increases reactivation risk 1

Clinical Algorithm for Ruling Out Other Infections

1. All patients with positive TST/IGRA:

   • Chest X-ray (mandatory) 1
   • Symptom assessment for active TB 1
   • If abnormal CXR or symptoms present → sputum AFB smear and culture 1

2. Before starting LTBI treatment or immunosuppression:

   • HBV, HCV, HIV serology 1
   • VZV serology (if no clear immunity history) 1
   • Baseline liver function tests (if risk factors present) 2

3. Geographic/exposure-based screening:

   • Strongyloides serology + eosinophil count (endemic area exposure) 1
   • Consider endemic fungal infections (region-specific) 1

4. Immunocompromised patients:

   • More comprehensive fungal screening may be warranted 1
   • Lower threshold for repeat testing if initial tests negative 1

Critical pitfall: Do not confuse non-tuberculous mycobacteria (NTM) with M. tuberculosis. IGRAs are preferred over TST in BCG-vaccinated individuals because they are not confounded by BCG or most NTM 1, 3. Culture with species identification is essential when AFB are detected 1.