What is the differential diagnosis (DDx) for a cavitary lung lesion in an immunosuppressed patient with rheumatoid arthritis (RA) on methotrexate (MTX) and sulfasalazine (SSZ), history of coronavirus disease 2019 (COVID-19) with secondary community-acquired pneumonia (CAP), and status post (s/p) bioprosthetic aortic valve replacement?

Differential Diagnosis for Cavitary Lung Lesion in an Immunosuppressed 87-Year-Old Male

In this immunosuppressed patient with rheumatoid arthritis on methotrexate and sulfasalazine, recent COVID-19 with secondary bacterial pneumonia, and a bioprosthetic valve, the differential diagnosis must prioritize infectious etiologies—particularly bacterial (including Nocardia, Pseudomonas, and Staphylococcus aureus), fungal (Aspergillus, endemic mycoses), and mycobacterial infections—followed by septic emboli from prosthetic valve endocarditis, with malignancy and rheumatoid nodules as less likely but important considerations.

High-Priority Infectious Etiologies

Bacterial Infections

• Nocardia asteroides is a critical consideration in immunosuppressed patients on methotrexate and causes cavitary pneumonia with high frequency 1
• Pseudomonas aeruginosa commonly produces cavitary lesions in immunocompromised hosts and should be strongly suspected given recent hospitalization for CAP 1
• Staphylococcus aureus (including MRSA) can cause necrotizing pneumonia with cavitation, particularly post-viral infections like COVID-19 1
• Rhodococcus equi is an emerging pathogen in immunosuppressed patients that frequently causes cavitary disease 1

Fungal Infections

• Invasive pulmonary aspergillosis frequently produces cavitation in immunosuppressed patients and is a major concern with methotrexate therapy 1
• Cryptococcosis can present with cavitary lesions, though less commonly than aspergillosis 1
• Endemic mycoses (Coccidioidomycosis, Histoplasmosis) should be considered based on geographic exposure, as they can cavitate in immunocompromised hosts 1

Mycobacterial Infections

• Mycobacterium tuberculosis must be ruled out, as cavitation is common in TB, particularly in patients with relatively preserved immunity 1
• Mycobacterium kansasii is frequently associated with cavitation and should be considered in the differential 1
• Mycobacterium avium complex (MAC) is less likely to cause cavitary disease but remains possible 1

Opportunistic Viral Infections

• Cytomegalovirus (CMV) pneumonitis can rarely present as cavitary lesions in immunosuppressed patients, though this is extremely uncommon 2

Critical Non-Infectious Considerations

Septic Emboli from Prosthetic Valve Endocarditis

• Prosthetic valve endocarditis with septic pulmonary emboli is a life-threatening diagnosis that must be urgently excluded given the bioprosthetic aortic valve 3
• Septic emboli can cause cavitary pulmonary infarcts, particularly in immunocompromised patients 3
• Blood cultures and echocardiography (preferably transesophageal) are essential 3

Rheumatoid-Associated Lung Disease

• Rheumatoid nodules can cavitate and should be considered, though typically occur in seropositive patients with subcutaneous nodules 4
• Methotrexate-induced pneumonitis rarely cavitates but should remain on the differential 5

Malignancy

• Primary lung cancer (particularly squamous cell carcinoma) commonly cavitates and must be excluded in this age group 4
• Lymphoma can rarely present with cavitary lesions in immunosuppressed patients 1

Pulmonary Infarction

• Non-septic pulmonary embolism with infarction can cavitate in approximately 5% of cases, particularly in immunocompromised patients 3

Diagnostic Approach Algorithm

Immediate Workup (Within 24 Hours)

• Blood cultures (×2-3 sets) before antibiotics to evaluate for bacteremia and endocarditis 6
• Sputum cultures including bacterial, fungal, and acid-fast bacilli (AFB) staining and culture 6
• Complete blood count with differential looking for leukocytosis, lymphopenia, or eosinophilia 6
• Inflammatory markers (CRP, ESR, procalcitonin) to assess infection severity 6
• Serum galactomannan and beta-D-glucan for fungal infection screening 1
• Transthoracic echocardiogram (with low threshold for transesophageal echo) to evaluate prosthetic valve 3

Bronchoscopy with Bronchoalveolar Lavage (BAL)

• Urgent bronchoscopy is indicated in immunosuppressed hosts with cavitary lesions to obtain definitive microbiologic diagnosis 6
• BAL should include: bacterial culture (including Nocardia), fungal culture, AFB smear and culture, viral PCR (including CMV), and cytology 5, 2
• Transbronchial biopsy may be considered if safe based on lesion location 6

Additional Imaging

• CT chest with contrast (if not already performed) to better characterize the cavity, assess for additional lesions, and evaluate for pulmonary emboli 4
• Consider CT-guided biopsy if bronchoscopy is non-diagnostic and clinical suspicion for malignancy is high 4

Empiric Treatment Considerations

Immediate Antibiotic Coverage

• Broad-spectrum antibiotics covering Pseudomonas, MRSA, and Nocardia should be initiated immediately given high mortality risk 6
• Suggested regimen: Vancomycin PLUS Piperacillin-tazobactam or Meropenem to cover MRSA, Pseudomonas, and other gram-negative organisms 5
• Add Trimethoprim-sulfamethoxazole if Nocardia is strongly suspected (though may need to hold sulfasalazine temporarily) 1

Antifungal Coverage

• Consider empiric voriconazole or isavuconazole if aspergillosis is strongly suspected based on imaging characteristics (e.g., halo sign, air-crescent sign) or positive galactomannan 1

Critical Pitfalls to Avoid

• Do not delay bronchoscopy waiting for non-invasive tests to return, as definitive diagnosis is essential in immunocompromised patients with cavitary disease 6
• Do not assume recent CAP explains the cavity—cavitation suggests either treatment failure, resistant organism, or alternative diagnosis 5
• Do not overlook endocarditis—prosthetic valve infection with septic emboli can be rapidly fatal if untreated 3
• Do not continue immunosuppression at current doses without infectious disease consultation—methotrexate may need to be held temporarily 5, 2

When to Escalate Care

• ICU transfer is indicated for respiratory distress, hemodynamic instability, or septic shock 6
• Infectious disease and pulmonology consultation should be obtained immediately 6
• Cardiothoracic surgery consultation if endocarditis with valve vegetation is confirmed 3