What is the differential diagnosis and recommended work‑up for patchy ground‑glass opacities on a chest CT?

Differential Diagnosis and Work-Up for Patchy Ground-Glass Opacities on Chest CT

Patchy ground-glass opacities (GGOs) require systematic evaluation based on the presence or absence of fibrotic features, distribution pattern, and clinical context—with the most common causes being atypical infections (32%), chronic infiltrative interstitial diseases (27%), drug-related pneumonitis, organizing pneumonia, and hypersensitivity pneumonitis. 1, 2

Initial Diagnostic Framework

The fundamental first step is determining whether fibrotic features accompany the GGOs, as this divides the differential diagnosis into two distinct pathways 3:

GGOs WITH Fibrotic Features (reticular lines, traction bronchiectasis/bronchiolectasis)

This pattern always indicates established lung fibrosis 3, 4:

• Nonspecific Interstitial Pneumonia (NSIP) - Bilateral symmetric GGOs with lower lung predominance, often with subpleural sparing 1, 3
• Idiopathic Pulmonary Fibrosis (IPF) - However, extensive GGO (>30% lung involvement) argues strongly against IPF and should prompt alternative diagnoses 3, 4
• Connective Tissue Disease-Related ILD - Consider scleroderma and rheumatoid arthritis when GGOs occur with fibrotic features 3
• Fibrotic Hypersensitivity Pneumonitis - Look for the "three-density pattern" (hypoattenuating, normal, and hyperattenuating lobules in close proximity), which is highly specific 3, 4

GGOs WITHOUT Fibrotic Features (isolated GGOs)

This pattern indicates inflammatory cells in the alveolar septum or lumen (alveolitis) 3, 4:

• Organizing Pneumonia (OP) - Multifocal patchy opacities with peribronchovascular and/or peripheral distribution; may show reversed halo sign 1
• Hypersensitivity Pneumonitis (HP) - Poorly defined small centrilobular nodules with bilateral GGO, mosaic attenuation on expiratory views 1, 5
• Drug-Related Pneumonitis - Various patterns including NSIP, OP, or diffuse alveolar damage (DAD) patterns in patients on molecular targeting agents or immune checkpoint inhibitors 1
• Simple Pulmonary Eosinophilia - Nonsegmental consolidation or GGO, unilateral or bilateral, transient and migratory with spontaneous resolution within 4 weeks 1
• Diffuse Alveolar Damage (DAD/ARDS pattern) - Extensive bilateral GGO with dependent airspace consolidation 1
• Atypical Infections - Most common cause in unselected cases (32%), including viral pneumonias, Pneumocystis, mycobacterial infections 2, 3

Critical Distribution Patterns for Diagnosis

Distribution analysis is essential for narrowing the differential 3:

• Subpleural and basal predominant - Consider UIP/IPF, organizing pneumonia, COVID-19 3
• Upper and mid-lung predominant - Strongly suggests hypersensitivity pneumonitis or sarcoidosis 3
• Peribronchovascular distribution - Argues against IPF; consider organizing pneumonia or drug-related pneumonitis 1, 3
• Random distribution - Most common pattern (43% of cases), does not differentiate underlying causes 2
• Centrilobular nodules with GGO - Highly suggestive of hypersensitivity pneumonitis in nonsmokers, especially with profuse poorly defined nodules affecting all lung zones 5, 3

Recommended Work-Up Algorithm

Step 1: Detailed Clinical History

• Smoking status - Nonsmokers with centrilobular nodules strongly suggest HP; current/former smokers may have DIP or RBILD 1, 5
• Medication review - Drug-related pneumonitis can occur 3-12 weeks after drug initiation with molecular targeting agents or immune checkpoint inhibitors 1, 5
• Exposure history - Birds, mold, hot tubs, feather bedding, occupational antigens for HP 5
• Duration of symptoms - Acute (days to weeks) versus chronic (months to years) 1, 6
• Geographic/endemic considerations - In TB-endemic regions or Asia, tuberculosis must be excluded first 5

Step 2: High-Resolution CT with Specific Protocol

• Obtain inspiratory AND expiratory views to assess for mosaic attenuation and air-trapping, which supports HP diagnosis 5, 3
• Assess for associated findings 3, 4:
  • "Paving stone-like" appearance (GGO + interlobular septal thickening) suggests COVID-19 or organizing pneumonia
  • Honeycombing indicates established fibrosis and favors UIP/IPF
  • Reversed halo sign may suggest organizing pneumonia or fungal infection

Step 3: Laboratory and Microbiologic Testing

• Sputum cultures, acid-fast bacilli smears, and nucleic acid amplification testing for TB - Mandatory in endemic regions or high-risk patients 5
• Bronchoalveolar lavage (BAL) with lymphocyte differential - BAL lymphocyte differential >20% supports HP diagnosis 5
• Avoid serum antigen-specific antibody testing for HP - Lacks sufficient evidence due to cross-reactivity, poor standardization, and frequent false-negative results 5

Step 4: Bronchoscopy with BAL ± Transbronchial Biopsy

• BAL is essential when HP is suspected - Lymphocyte differential is the key diagnostic parameter 5
• Transbronchial biopsy increases diagnostic yield when combined with BAL, particularly in fibrotic HP 5
• Consider timing - Most diagnoses in research cohorts were confirmed within 7 days of imaging (mean 6.9 days) 2

Step 5: Empirical Treatment Trial (Selected Cases)

• If organizing pneumonia is strongly suspected based on imaging pattern (peripheral/peribronchovascular distribution, reversed halo sign) and clinical context, consider high-dose corticosteroid trial with expected improvement within 48-72 hours 3
• Immediate antigen avoidance is the cornerstone for HP - Clinical improvement after medical therapy alone should NOT be used to confirm diagnosis 5
• Discontinue offending medication immediately if drug-related pneumonitis is suspected 5

Common Pitfalls to Avoid

• Do not assume infectious etiology without considering HP, especially in nonsmokers with exposure history and centrilobular nodules 5
• Do not delay TB evaluation in endemic regions or high-risk patients 5
• Do not overlook recent medication changes - Drug-related pneumonitis can present 3-12 weeks after initiation 5
• Do not diagnose IPF when extensive GGO (>30%) is present - This pattern argues against IPF and should prompt consideration of NSIP, organizing pneumonia, or HP 3, 4
• Do not confuse GGO with consolidation - In GGO, bronchial and vascular margins remain visible; in consolidation, bronchovascular structures are obscured 7
• Do not rely on lobular distribution alone - Distribution at the lobular level (geographic, centrilobular, or random) does not reliably differentiate underlying causes 2