What is the differential diagnosis for a centrilobular tree-in-bud appearance with ground-glass opacities on High-Resolution Computed Tomography (HRCT)?

Differential Diagnosis of Centrilobular Tree-in-Bud with Ground-Glass Opacities on HRCT

The combination of centrilobular tree-in-bud pattern with ground-glass opacities most commonly indicates hypersensitivity pneumonitis, followed by infectious etiologies including tuberculosis, nontuberculous mycobacteria, and atypical bacterial infections. 1

Primary Diagnostic Considerations

Hypersensitivity Pneumonitis (Most Likely)

• Profuse poorly defined centrilobular nodules of ground-glass opacity affecting all lung zones is highly suggestive of hypersensitivity pneumonitis in the appropriate clinical context. 1
• The presence of centrilobular nodules with middle and upper lobe predominance, combined with ground-glass attenuation, strongly favors hypersensitivity pneumonitis over other fibrotic lung diseases. 1
• The three-density pattern (hypoattenuating, normal, and hyperattenuating lobules coexisting) on inspiratory imaging is highly specific for hypersensitivity pneumonitis when associated with these findings. 1
• Ill-defined centrilobular nodules of ground-glass attenuation pathologically represent peribronchiolar inflammation, which is characteristic of subacute hypersensitivity pneumonitis. 2
• Critical pitfall: Always obtain detailed exposure history to birds, mold, hot tubs, or occupational antigens, as this dramatically increases diagnostic confidence. 1

Infectious Etiologies (Second Most Common)

Mycobacterial Infections

• Mycobacterium tuberculosis commonly presents with centrilobular tree-in-bud nodules and bronchial wall thickening, though ground-glass opacity is less prominent than in hypersensitivity pneumonitis. 2, 3
• Nontuberculous mycobacteria (MAC, M. kansasii) demonstrate tree-in-bud appearance with centrilobular nodules in the majority of cases. 2
• Upper lobe predominance with cavitation favors mycobacterial infection over hypersensitivity pneumonitis. 3

Atypical Bacterial Infections

• Mycoplasma pneumoniae pneumonia shows centrilobular nodules with tree-in-bud appearance and bronchial wall thickening in approximately 85% of cases. 2
• The tree-in-bud pattern pathologically correlates with plugging of small airways with mucus, pus, or fluid, which occurs in bacterial infections. 2

Small Airways Disease

Diffuse Panbronchiolitis

• Presents with centrilobular tree-in-bud nodules and bronchial wall thickening in the majority of patients. 2
• Distinguished by chronic sinusitis and progressive airflow obstruction on pulmonary function testing. 2

Aspiration Bronchiolitis

• Diffuse aspiration bronchiolitis demonstrates centrilobular nodules with tree-in-bud appearance in all cases. 2
• Look for risk factors including dysphagia, neurologic disorders, or altered consciousness. 2

Less Common but Important Considerations

Vasculitic/Autoimmune Disorders

• Microscopic polyangiitis shows ill-defined centrilobular nodules of ground-glass attenuation in approximately 56% of cases, representing peribronchiolar inflammation or hemorrhagic deposition. 2
• Churg-Strauss syndrome can present with similar findings in one-third of patients. 2
• Systemic lupus erythematosus demonstrates this pattern in the majority of pulmonary involvement cases. 2

Allergic Bronchopulmonary Aspergillosis

• Presents with centrilobular tree-in-bud nodules and bronchial wall thickening in two-thirds of cases. 2
• Associated findings include central bronchiectasis and mucoid impaction (gloved finger sign). 4

Respiratory Bronchiolitis-Associated Interstitial Lung Disease

• All cases show ill-defined centrilobular nodules of ground-glass attenuation. 2
• Critical distinction: Almost exclusively occurs in current smokers with upper lobe predominance. 1

Diagnostic Algorithm

Step 1: Assess Distribution Pattern

• Upper/middle lobe predominance + mosaic attenuation → strongly favors hypersensitivity pneumonitis. 1
• Upper lobe predominance with cavitation → consider mycobacterial infection. 3
• Random distribution → consider miliary tuberculosis or hematogenous spread. 3

Step 2: Evaluate Associated CT Features

• Three-density sign present → hypersensitivity pneumonitis (highly specific). 1
• Extensive ground-glass opacity (>30% lung involvement) without basal predominance → hypersensitivity pneumonitis, NSIP, or organizing pneumonia rather than usual interstitial pneumonia. 1
• Cavitation present → mycobacterial infection most likely. 3
• Bronchial wall thickening prominent → infectious etiology or diffuse panbronchiolitis. 2

Step 3: Integrate Clinical Context

• Exposure history (birds, mold, hot tubs, occupational) → hypersensitivity pneumonitis. 1
• Immunosuppression or transplant recipient → consider tuberculosis (miliary pattern associated with 50% mortality). 3
• Smoking history → respiratory bronchiolitis-associated interstitial lung disease. 1, 2
• Chronic sinusitis → diffuse panbronchiolitis. 2
• Eosinophilia → allergic bronchopulmonary aspergillosis or Churg-Strauss syndrome. 2

Step 4: Pursue Targeted Workup

• Bronchoalveolar lavage with lymphocyte differential: >20% lymphocytes supports hypersensitivity pneumonitis (though not required for diagnosis). 1
• Mycobacterial cultures and acid-fast bacilli staining when infection suspected. 3
• Serum precipitins or specific IgG antibodies to suspected antigens in hypersensitivity pneumonitis. 1
• Transbronchial biopsy showing granulomas, giant cells, and inflammatory bronchiolitis increases diagnostic yield, particularly when combined with bronchoalveolar lavage. 1

Critical Pitfalls to Avoid

• Do not diagnose idiopathic pulmonary fibrosis when centrilobular nodules are present—this finding strongly suggests an alternative diagnosis, most commonly hypersensitivity pneumonitis. 1
• Expiratory imaging is essential to confirm air trapping in suspected hypersensitivity pneumonitis, as inspiratory images alone may be indeterminate. 1
• The tree-in-bud pattern is fairly specific for infectious causes when well-defined, but ill-defined centrilobular ground-glass nodules more commonly represent hypersensitivity pneumonitis. 4, 2
• In immunocompromised patients, miliary nodules on HRCT carry a 50% mortality rate and require urgent evaluation for disseminated tuberculosis. 3