Do ground glass opacities (GGOs) on a chest computed tomography (CT) scan always indicate an infectious cause?

Ground Glass Opacities Do Not Always Indicate Infection

Ground glass opacities (GGOs) on chest CT are a nonspecific finding that can represent infectious, inflammatory, fibrotic, vascular, drug-related, and neoplastic processes—infection is only one of many possible etiologies. 1, 2, 3

Understanding What GGOs Represent Pathologically

GGOs reflect several distinct pathologic processes, not just infection: 3, 4

• Partial filling of air spaces (as in pneumonia, edema, or hemorrhage) 3
• Inflammatory or fibrotic interstitial thickening (as in hypersensitivity pneumonitis or early fibrosis) 3
• Increased capillary blood volume (as in vascular disorders) 3
• Inflammatory cells in alveolar septum or lumen (alveolitis) when GGOs appear isolated without fibrotic features 5, 1

Major Non-Infectious Causes You Cannot Miss

Interstitial Lung Diseases

• Hypersensitivity pneumonitis presents with profuse poorly defined centrilobular nodules of ground-glass opacity affecting all lung zones, particularly in nonsmokers 6
• Organizing pneumonia shows multifocal patchy alveolar opacities with peribronchovascular distribution, often with a reversed halo sign 1, 7
• Idiopathic pulmonary fibrosis may show GGOs, though extensive ground glass opacity (>30% of lung involvement) argues against IPF and should prompt consideration of alternative diagnoses 1, 6
• Nonspecific interstitial pneumonia (NSIP) frequently presents with GGOs without basal or peripheral predominance 1

Drug-Related and Radiation Causes

• Drug-related pneumonitis from molecular targeting agents (EGFR-TKIs, mTOR inhibitors) and immune checkpoint inhibitors can present with GGOs in organizing pneumonia or NSIP-like patterns 1, 7
• Radiation pneumonitis shows GGOs within the radiation portal, typically appearing 3-12 weeks after radiation exposure 1

Vascular and Hemorrhagic Causes

• Pulmonary veno-occlusive disease (PVOD) demonstrates centrilobular GGO significantly more frequently than idiopathic pulmonary arterial hypertension; when combined with septal lines and mediastinal adenopathy, this has 100% specificity for PVOD 7
• Alveolar hemorrhage presents with bilateral patchy GGOs in middle and lower lung zones 1
• Hydrostatic pulmonary edema causes expansion of connective tissue space around conducting airways and vessels, creating peribronchovascular haziness with Kerley lines 1, 7

Infectious Causes (When GGOs DO Indicate Infection)

While infection is an important consideration, it represents only a subset of GGO etiologies: 2, 8

• Viral pneumonias (COVID-19, influenza, cytomegalovirus) show bilateral, peripheral, ground-glass or mixed consolidative patterns 5, 2
• Invasive fungal infections in immunocompromised patients show small nodules (1-3 cm) surrounded by a halo (ground-glass opacification), typically localized close to vessels, representing perifocal hemorrhage 5
• Pneumocystis jiroveci pneumonia in immunocompromised hosts 8
• Atypical infections may demonstrate peribronchovascular infiltration patterns 7

Critical Diagnostic Algorithm

Step 1: Assess Distribution Pattern

• Bilateral, peripheral, lower lobe predominant → Consider viral pneumonia (especially COVID-19), organizing pneumonia, or drug reaction 5, 1
• Peribronchovascular distribution → Organizing pneumonia, hypersensitivity pneumonitis, or drug-related pneumonitis 7
• Centrilobular nodules with GGO → Hypersensitivity pneumonitis or respiratory bronchiolitis-ILD 1, 6
• Nodules with halo sign → Invasive fungal infection in immunocompromised patients 5

Step 2: Look for Associated Findings

• GGOs with reticular lines and traction bronchiectasis → Always indicates lung fibrosis, not acute infection 5, 1
• Septal lines + adenopathy + centrilobular GGO → 100% specific for PVOD 7
• Reversed halo sign → Organizing pneumonia or fungal infection 7
• Three-density pattern (hypoattenuating, normal, and hyperattenuating lobules in close proximity) → Highly specific for fibrotic hypersensitivity pneumonitis 1, 6

Step 3: Obtain Critical Clinical Context

• Recent medication changes (within 3-12 weeks) → Drug-related pneumonitis 6
• Radiation therapy history → Radiation pneumonitis 1
• Organic antigen exposure history → Hypersensitivity pneumonitis 6
• Immunocompromised status → Consider fungal infection, Pneumocystis, or drug toxicity 5, 8
• TB-endemic region or high-risk patient → Tuberculosis must be excluded first 6

Step 4: Perform Targeted Workup Based on Leading Diagnosis

• For suspected HP: Obtain detailed exposure history, perform BAL with lymphocyte differential (>20% supports HP), and obtain inspiratory/expiratory CT to assess for mosaic attenuation and air-trapping 6
• For suspected infection: Obtain sputum cultures, acid-fast bacilli smears, nucleic acid amplification testing for TB, and consider fungal markers (galactomannan, beta-D-glucan) in immunocompromised patients 5, 6
• For suspected drug reaction: Review medication timeline and consider discontinuing offending agent immediately 6

Common Pitfalls to Avoid

• Do not assume infectious etiology without considering hypersensitivity pneumonitis, especially in nonsmokers with exposure history 6
• Do not delay TB evaluation in endemic regions or high-risk patients 6
• Do not overlook recent medication changes, as drug-related pneumonitis can occur 3-12 weeks after drug initiation 6
• Do not diagnose IPF when extensive ground-glass opacity (>30% of lung involvement) is present; this argues against IPF and should prompt consideration of alternative diagnoses 6
• Remember that early disease may show normal imaging: 56% of early COVID-19 patients had normal CT, and patients with biopsy-proven hypersensitivity pneumonitis, sarcoidosis, and IPF may have normal HRCT 5