What are the differential diagnoses for a patient presenting with ground glass opacity on computed tomography (CT) scan?

Differential Diagnoses for Ground Glass Opacity on CT

Ground glass opacity (GGO) on CT represents a diffuse homogeneous increase in lung density where vessels and bronchial walls remain visible, and the differential diagnosis must be systematically approached based on distribution pattern, associated findings, and clinical context. 1, 2

Key Diagnostic Framework

The presence or absence of fibrotic features fundamentally divides the differential:

GGO WITH Reticular Lines and Traction Bronchiectasis = Fibrosis

When GGO occurs with reticular lines and traction bronchiectasis/bronchiolectasis, it always indicates lung fibrosis. 1, 2 Consider:

• Idiopathic Pulmonary Fibrosis (IPF) - but extensive GGO (>30% lung involvement) argues against IPF and should prompt alternative diagnoses 1, 2
• Nonspecific Interstitial Pneumonia (NSIP) - typically shows GGO without basal or peripheral predominance, often with extensive ground-glass opacification and subpleural sparing 1, 2
• Fibrotic Hypersensitivity Pneumonitis - look for the "three-density pattern" (hypoattenuating, normal, and hyperattenuating lobules in close proximity), which is highly specific 2, 3
• Connective Tissue Disease-related ILD - particularly scleroderma and rheumatoid arthritis 1
• Asbestosis - similar to IPF but with parenchymal bands and pleural plaques 1

GGO WITHOUT Fibrotic Features = Alveolitis/Inflammation

Isolated GGO is usually associated with inflammatory cells in the alveolar septum or alveolar lumen (alveolitis). 1, 2 Consider:

Infectious Causes

• COVID-19 pneumonia - multiple patchy subpleural GGOs with "paving stone-like" appearance (GGO with interlobular septal thickening), bilateral distribution 1, 2
• Pneumocystis pneumonia - diffuse bilateral perihilar infiltrates, patchy GGO with peripheral sparing 2
• Viral pneumonias - influenza, parainfluenza, adenovirus, respiratory syncytial virus, cytomegalovirus 1, 4
• Mycoplasma and Chlamydia pneumonia 1
• Mycobacterial infections - including nontuberculous mycobacterial disease 2

Non-Infectious Inflammatory Processes

• Organizing Pneumonia (OP) - patchy consolidation or GGO in predominantly peripheral or peribronchovascular distribution 2, 3
• Hypersensitivity Pneumonitis (acute/subacute) - profuse poorly defined centrilobular nodules with widespread GGO, middle and upper lobe predominance, absence of honeycombing 1, 2, 5
• Desquamative Interstitial Pneumonitis (DIP) - characterized by extensive GGOs, often regresses with treatment 1, 2, 3
• Respiratory Bronchiolitis-ILD - GGO often with centrilobular nodules 1, 3
• Diffuse Alveolar Damage - extensive bilateral GGO with dependent consolidation and traction bronchiectasis 2, 3
• Drug-induced pneumonitis - from molecular targeting agents, immune checkpoint inhibitors, or other medications; occurs 3-12 weeks after drug initiation 3, 5
• Radiation pneumonitis - GGO within radiation portal, appears 3-12 weeks after exposure 3

Other Non-Infectious Causes

• Pulmonary edema (hydrostatic) - hazy opacities with Kerley lines, sometimes batwing appearance 3
• Alveolar hemorrhage - bilateral patchy GGO in middle and lower lung zones 2, 3
• Pulmonary alveolar proteinosis 6
• Eosinophilic pneumonia 3
• Vaping-related lung injury 4
• Pulmonary infarction 4

Critical Diagnostic Clues

Distribution Patterns Matter

• Subpleural and basal predominant = consider UIP/IPF, organizing pneumonia, COVID-19 1, 2
• Upper and mid-lung predominant = consider hypersensitivity pneumonitis, sarcoidosis 1
• Peribronchovascular = suggests alternative to IPF 1
• Diffuse without specific distribution = consider infection, edema, alveolar hemorrhage 2, 3

Associated CT Features

• "Paving stone-like" appearance (GGO + interlobular septal thickening) = COVID-19 or organizing pneumonia 1, 2
• Centrilobular nodules = hypersensitivity pneumonitis, respiratory bronchiolitis-ILD, infection 1, 2, 5
• Mosaic attenuation with air-trapping = hypersensitivity pneumonitis, small airway disease 2, 5
• Honeycombing = established fibrosis, favors UIP/IPF over other diagnoses 1
• Consolidation within GGO = organizing pneumonia, COVID-19 progression 1, 2

Common Pitfalls to Avoid

• Do not assume infectious etiology without considering hypersensitivity pneumonitis, especially in nonsmokers with exposure history to organic antigens 5
• Do not diagnose IPF when extensive GGO (>30%) is present - this pattern strongly suggests DIP, NSIP, organizing pneumonia, or hypersensitivity pneumonitis instead 1, 5
• Do not delay tuberculosis evaluation in endemic regions or high-risk patients when centrilobular nodules are present 5
• Do not overlook recent medication changes - drug-related pneumonitis can occur weeks after drug initiation 5
• Confirm subpleural opacities with prone inspiratory views to exclude dependent atelectasis 1
• Remember physiological causes - poor ventilation of dependent lung areas and expiratory effects can mimic pathologic GGO 7