What is the differential diagnosis for a patient presenting with symptoms suggestive of tuberculosis (TB), including cough, fever, weight loss, and night sweats?

Differential Diagnosis for Tuberculosis

When a patient presents with cough, fever, weight loss, and night sweats suggestive of TB, the differential diagnosis must include bacterial pneumonia (especially anaerobic infections), fungal infections (histoplasmosis, coccidioidomycosis, blastomycosis), lung cancer, and nontuberculous mycobacterial infections. 1, 2

Primary Differential Considerations

Bacterial Pneumonia

• Anaerobic bacterial pneumonia can closely mimic TB with similar constitutional symptoms and radiographic findings, particularly when cavitary lesions are present 2
• Community-acquired bacterial pneumonia may present with cough and fever but typically has a more acute onset (days rather than weeks) compared to TB's insidious progression 1

Fungal Infections

• Histoplasmosis, coccidioidomycosis, and blastomycosis are endemic mycoses that can present identically to TB with chronic cough, fever, night sweats, weight loss, and cavitary lung lesions 1, 2
• These fungal infections are particularly important to consider based on geographic exposure history and travel patterns 1

Malignancy

• Lung carcinoma (particularly adenocarcinoma and squamous cell carcinoma) can mimic TB radiographically and clinically, presenting with chronic cough, weight loss, and hemoptysis 2, 3
• Critical caveat: TB and lung cancer can coexist in the same patient, so identifying one does not exclude the other 2
• Pulmonary nodules require careful evaluation, as tuberculomas and adenocarcinomas can appear identical on imaging, with features like pleural indentation or notching being nonspecific 3

Nontuberculous Mycobacterial (NTM) Infections

• When AFB smears are positive but nucleic acid amplification testing is negative (after excluding PCR inhibitors), NTM infection should be presumed rather than TB 4
• NTM infections can present with identical symptoms and radiographic findings to TB 4

Key Diagnostic Discriminators

Clinical Features That Increase TB Likelihood

• Duration of symptoms: TB typically presents with symptoms lasting ≥2-3 weeks, whereas bacterial pneumonia is more acute 1, 4
• Constitutional symptoms: The combination of fever, night sweats, hemoptysis, and weight loss significantly increases TB probability, particularly in HIV-infected patients 1
• Risk factor assessment: Foreign-born from endemic countries, HIV infection, homelessness, incarceration, immunosuppression, diabetes, silicosis, end-stage renal disease, and recent TB contact all substantially elevate TB likelihood 1, 5, 4, 6

Radiographic Patterns

• Classic TB findings: Upper lobe cavitary disease, apical posterior segment infiltrates, hilar/mediastinal adenopathy, and fibrotic lesions suggest TB 5, 7, 4
• Atypical presentations: Immunocompromised patients (especially those with AIDS and very low CD4 counts) may have normal or atypical chest radiographs, making diagnosis more challenging 5
• Lower lobe lesions: More common in elderly patients with TB compared to younger patients 1

Microbiological Differentiation

• Three sputum specimens collected on different days for AFB smear microscopy and mycobacterial culture are essential, as culture remains the gold standard 4, 8
• Nucleic acid amplification testing (NAA/Xpert MTB/RIF) should be performed on at least one specimen to enable diagnosis within 1-2 days 5, 4
• Interpretation algorithm:
  • AFB smear positive + NAA positive = presume TB (>95% positive predictive value) 4
  • AFB smear negative + NAA positive = consider additional specimen testing; if two or more NAA-positive, presume TB 4
  • AFB smear positive + NAA negative = test for PCR inhibitors; if no inhibitors and repeat specimen remains smear-positive/NAA-negative, presume NTM infection 4

Common Pitfalls to Avoid

• Never exclude TB based on negative AFB smears alone, as smear sensitivity is limited and culture remains the gold standard 4
• Do not assume a single diagnosis when evaluating pulmonary nodules, as tuberculoma and lung cancer can coexist 2
• Avoid delaying empiric treatment in high-risk patients with classic symptoms while awaiting diagnostic confirmation, as this increases mortality and transmission risk 5, 7
• Do not overlook extrapulmonary TB, which can affect any organ system and may require tissue biopsy for diagnosis 8, 2, 9
• Remember that elderly patients may present atypically with less fever, sweating, and hemoptysis, and are less likely to have positive tuberculin skin tests 1