What are the differential diagnoses for ground glass opacities on computed tomography (CT) in a patient?

Differential Diagnoses for Ground Glass Opacities on CT

Ground glass opacities (GGOs) on CT represent a nonspecific finding with a broad differential diagnosis that must be narrowed by analyzing the distribution pattern, associated CT features, extent of involvement, and clinical context. 1

Key Diagnostic Framework

The approach to GGOs requires systematic evaluation of four critical features that dramatically narrow the differential:

1. Extent of Ground Glass Involvement

• If GGO involves >30% of lung parenchyma, this argues strongly against idiopathic pulmonary fibrosis (IPF) and should prompt consideration of desquamative interstitial pneumonitis (DIP), nonspecific interstitial pneumonia (NSIP), organizing pneumonia, or hypersensitivity pneumonitis 2, 1
• Extensive bilateral GGO suggests acute processes including viral pneumonias (COVID-19, influenza, cytomegalovirus), Pneumocystis pneumonia, pulmonary edema, or alveolar hemorrhage 1, 3

2. Distribution Pattern Analysis

Subpleural/Peripheral Distribution:

• COVID-19 pneumonia (multiple patchy subpleural GGOs with "paving stone" appearance from interlobular septal thickening) 1
• Organizing pneumonia (patchy consolidation or GGO in peripheral or peribronchovascular distribution) 1
• Usual interstitial pneumonia/IPF (though typically shows reticular pattern with honeycombing rather than extensive GGO) 1

Peribronchovascular Distribution:

• Organizing pneumonia (most common cause with this pattern, showing multifocal patchy opacities extending along bronchovascular bundles) 4
• Hypersensitivity pneumonitis in subacute phase (poorly defined centrilobular nodules with bilateral GGO) 4
• Drug-related pneumonitis (particularly with immune checkpoint inhibitors, EGFR-TKIs, mTOR inhibitors) 4
• Pulmonary veno-occlusive disease (centrilobular GGO with septal lines and mediastinal adenopathy has 100% specificity) 4

Centrilobular Pattern:

• Hypersensitivity pneumonitis (profuse poorly defined centrilobular nodules of ground-glass opacity affecting all lung zones in nonsmokers) 5
• Respiratory bronchiolitis-interstitial lung disease (in smokers) 2

3. Associated CT Features That Refine Diagnosis

GGO with reticular lines and traction bronchiectasis/bronchiolectasis:

• Always indicates lung fibrosis (fibrotic NSIP, IPF with ground glass component, fibrotic hypersensitivity pneumonitis) 2, 1

"Paving stone" appearance (GGO with interlobular septal thickening):

• COVID-19 pneumonia (characteristic finding) 1
• Organizing pneumonia 1

"Reversed halo sign" (GGO surrounded by ring of consolidation):

• Organizing pneumonia 4
• Fungal pneumonia, particularly mucormycosis 1

"Three-density pattern" (hypoattenuating, normal, and hyperattenuating lobules in close proximity):

• Highly specific for fibrotic hypersensitivity pneumonitis 1

Mosaic attenuation with air-trapping on expiratory views:

• Hypersensitivity pneumonitis (supports diagnosis when combined with centrilobular nodules) 1, 5
• Small airway disease 1

Centrilobular GGO + septal lines + mediastinal adenopathy:

• 100% specific for pulmonary veno-occlusive disease in patients with pulmonary hypertension 4

4. Clinical Context-Specific Differentials

Acute Presentation (<4 weeks):

• Viral pneumonias: COVID-19, influenza, cytomegalovirus 3
• Pneumocystis pneumonia (diffuse bilateral perihilar infiltrates with peripheral sparing) 1
• Bacterial atypical infections 5
• Pulmonary edema (hydrostatic or cardiogenic) 6
• Alveolar hemorrhage (bilateral patchy GGOs in middle and lower lung zones) 1
• Acute hypersensitivity pneumonitis 2
• Drug-induced pneumonitis (occurs 3-12 weeks after drug initiation) 5
• Vaping-associated lung injury 3
• Pulmonary infarction 3

Subacute to Chronic Presentation:

• Nonspecific interstitial pneumonia (NSIP) 2, 1
• Organizing pneumonia (idiopathic or secondary) 1, 4
• Hypersensitivity pneumonitis (subacute or chronic) 2, 5
• Desquamative interstitial pneumonitis (extensive GGOs) 2, 1
• Respiratory bronchiolitis-interstitial lung disease (in smokers) 2
• Drug-induced pneumonitis 5, 4
• Sarcoidosis 2
• Alveolar proteinosis 6
• Radiation pneumonitis 6

In TB-Endemic Regions or High-Risk Patients:

• Tuberculosis and nontuberculous mycobacterial infections must be excluded first given high prevalence 5

Critical Diagnostic Pitfalls to Avoid

• Do not assume infectious etiology without considering hypersensitivity pneumonitis, especially in nonsmokers with potential antigen exposure history 5
• Do not delay tuberculosis evaluation in endemic regions or high-risk patients; obtain sputum cultures, acid-fast bacilli smears, and nucleic acid amplification testing immediately 5
• Do not overlook recent medication changes within the past 3-12 weeks, as drug-related pneumonitis is increasingly common with newer targeted therapies and immunotherapies 5, 4
• Do not confuse GGO with mosaic attenuation from vascular or airway disease; evaluate vessel caliber and obtain expiratory scans to assess for air-trapping 7
• Isolated GGO without fibrotic features (no traction bronchiectasis) usually indicates inflammatory cells in alveolar septum or lumen (alveolitis), not established fibrosis 2, 1

Algorithmic Diagnostic Approach

Step 1: Quantify GGO extent

• If >30% involvement → Consider DIP, NSIP, organizing pneumonia, HP, acute infections, pulmonary edema, alveolar hemorrhage 2, 1
• If <30% with reticular pattern and honeycombing → Consider IPF 2

Step 2: Analyze distribution

• Subpleural → COVID-19, organizing pneumonia, UIP 1
• Peribronchovascular → Organizing pneumonia, HP, drug-induced 4
• Centrilobular → HP (especially if nonsmoker), RB-ILD (if smoker) 5

Step 3: Identify associated features

• Traction bronchiectasis → Fibrotic process 2, 1
• Paving stone → COVID-19, organizing pneumonia 1
• Reversed halo → Organizing pneumonia, fungal infection 1, 4
• Three-density pattern → Fibrotic HP 1
• Septal lines + adenopathy + centrilobular GGO → PVOD 4

Step 4: Obtain targeted history

• Antigen exposures (birds, mold, hot tubs) → HP 5
• Medication history (past 3-12 weeks) → Drug-induced 5
• Smoking status → RB-ILD vs HP 5
• TB risk factors/endemic area → Mycobacterial infection 5
• Immunosuppression → Opportunistic infections 1

Step 5: Perform high-resolution CT with expiratory views to assess for air-trapping and mosaic attenuation 5

Step 6: Consider bronchoalveolar lavage with lymphocyte differential (>20% supports HP diagnosis) and transbronchial biopsy to increase diagnostic yield 5