What is the differential diagnosis of an infected pulmonary mass?

Differential Diagnosis of an Infected Pulmonary Mass

The differential diagnosis of an infected pulmonary mass must prioritize invasive fungal infections (particularly aspergillosis), mycobacterial infections (tuberculosis and nontuberculous mycobacteria), bacterial lung abscess, and necrotizing malignancy, with the specific diagnosis guided by the patient's immune status, CT imaging characteristics, and microbiological findings.

Primary Infectious Etiologies

Fungal Infections

Invasive Aspergillosis is the most critical fungal consideration, particularly in immunocompromised patients 1. CT findings include:

• Nodular or cavitary lesions with the "halo sign" (ground-glass attenuation surrounding a nodule) indicating early invasive disease 1
• Air-crescent sign suggesting later-stage infection with necrosis 1, 2
• Fungus balls (aspergillomas) appearing as solid rounded masses within cavities, separated from the cavity wall by an airspace 1

Chronic Pulmonary Aspergillosis (CPA) should be considered in patients with pre-existing lung cavities from tuberculosis, sarcoidosis, or other chronic lung disease 1, 3. The diagnosis requires positive Aspergillus precipitins (>95% sensitivity), respiratory samples growing Aspergillus species, and/or positive Aspergillus PCR from respiratory fluids 1.

Endemic fungi must be considered based on geographic exposure and travel history 1, 2:

• Chronic cavitary pulmonary histoplasmosis
• Paracoccidioidomycosis
• Coccidioidomycosis

Mycobacterial Infections

Tuberculosis and nontuberculous mycobacterial (NTM) infections are the usual differential diagnosis for any cavitary lung disease 1, 4. Key points:

• May precede, follow, or occur simultaneously with fungal infections 1
• Upper lobe predominance with nodular or cavitary lesions is characteristic 4
• Pulmonary samples for acid-fast bacilli smear, nucleic acid amplification, and culture are essential 1
• Diagnosing mycobacterial infection does not exclude concurrent fungal disease 1

Bacterial Infections

Conventional bacterial pathogens can infect persistent lung cavities 1:

• Streptococcus pneumoniae, Haemophilus influenzae, Staphylococcus aureus 1
• Pseudomonas aeruginosa causes cavitation in 4-15% of severe pneumonias and requires specific coverage 2
• Anaerobic bacteria in lung abscesses from aspiration or septic emboli 2
• Nocardia species in immunocompromised patients 1

Lung abscess characteristics on imaging include 2:

• Thick-walled cavities (>4mm wall thickness)
• Air-fluid levels
• Proximity to pleura suggesting aspiration or septic emboli

Pneumocystis Pneumonia (PCP)

PCP should be considered in immunocompromised patients, particularly those with HIV (CD4 <200), chronic corticosteroid use, or other immunosuppression 4. Typical features include:

• Diffuse bilateral perihilar infiltrates with ground-glass attenuation 4
• Upper lobe predominance with cystic changes is atypical but possible 4
• Requires trimethoprim-sulfamethoxazole 15-20 mg/kg/day with prednisone if PaO2 <70 mmHg 4

Non-Infectious Etiologies

Malignancy

Necrotizing lung cancer is a critical differential diagnosis 1. Consider:

• Primary lung malignancy with central necrosis
• Malignancy-associated granulomatosis mimicking infectious processes 5
• Lymphoproliferative disorders that can be very challenging to distinguish from sarcoidosis 5

Vasculitis and Inflammatory Conditions

Granulomatosis with polyangiitis (Wegener's) presents with cavitary nodules and requires autoantibody testing 6, 5.

Rheumatoid nodules can cavitate and become secondarily infected 1.

Sarcoidosis typically shows non-caseating granulomas but can have atypical presentations requiring exclusion of infections 5.

Other Considerations

• Pulmonary infarction from thromboembolic disease 1
• Drug-induced granulomatosis from TNF-α antagonists, immune checkpoint inhibitors, or other medications 5
• Hypersensitivity pneumonitis and chronic beryllium disease in appropriate exposure contexts 6, 5

Diagnostic Algorithm

Imaging Priority

High-resolution CT chest is mandatory and far superior to conventional radiography 1:

• Detects pathological findings in ~50% of patients with normal chest X-rays 1
• Should be obtained within 24 hours of clinical indication 1
• Contrast enhancement may increase diagnostic specificity for mold infections 1

Microbiological Workup

Bronchoalveolar lavage (BAL) provides the highest diagnostic yield 1, 7, 2:

• Send samples for bacterial culture (including anaerobes), fungal culture, mycobacterial smear and culture, galactomannan testing, and PCR assays 1
• Isolation of Aspergillus species from respiratory specimens in severely immunocompromised patients typically indicates invasive disease, not colonization 1
• Combined galactomannan and Aspergillus PCR positivity in BAL makes pulmonary aspergillosis highly likely 1

Blood cultures (two sets) should be obtained but may be negative in localized pulmonary infections 7, 2.

Sputum cultures are less reliable than BAL but may be useful in patients who cannot tolerate bronchoscopy 7.

Special Considerations

In febrile neutropenic patients, the detection rate from BAL is 25-50%, with polymicrobial infections common (molds plus bacteria in 12% of cases) 1.

False-positive galactomannan can occur with β-lactam antibiotics (piperacillin-tazobactam, carbapenems), enteral nutrition, and certain blood product conditioning fluids 1.

Prior antifungal therapy reduces sensitivity of both galactomannan and PCR assays 1.

Critical Pitfalls to Avoid

• Do not assume fungal isolates represent colonization in immunocompromised or elderly patients with chronic symptoms 7
• Do not rely on blood cultures alone—respiratory sampling is essential as blood cultures may miss polymicrobial infections 2
• Do not delay bronchoscopy in deteriorating patients waiting for sputum results 2
• Increasing infiltrate volume during the first week of treatment may occur despite effective antifungal therapy and should not automatically indicate treatment failure 1, 7
• Do not order follow-up CT scans <7 days after starting treatment as early radiographic progression does not indicate refractoriness 1