What are the differential diagnoses and recommended work‑up for diffuse centrilobular ground‑glass opacities that are most prominent in the upper lung zones, suggesting an atypical infectious or inflammatory process?

Differential Diagnoses for Centrilobular Ground-Glass Opacities with Upper Lung Predominance

Hypersensitivity pneumonitis (HP) is the most likely diagnosis when profuse, poorly defined centrilobular ground-glass nodules affect all lung zones with upper lobe predominance in a nonsmoker, and this should be your primary working diagnosis until proven otherwise. 1, 2

Primary Differential Diagnoses

Hypersensitivity Pneumonitis (Most Likely)

• Profuse poorly defined centrilobular nodules of ground-glass opacity affecting all lung zones is highly suggestive of HP in the appropriate clinical context 1, 2
• The combination of centrilobular nodules with middle and upper lobe predominance strongly favors HP over other fibrotic lung diseases 3
• Look specifically for the three-density pattern (hypoattenuating, normal, and hyperattenuating lobules coexisting on inspiratory imaging)—this finding is highly specific for HP when present 2, 3
• Inspiratory mosaic attenuation with air-trapping associated with centrilobular nodules supports this diagnosis 1, 2

Atypical Infections (Second Most Common)

• Mycoplasma pneumoniae, tuberculosis, and nontuberculous mycobacterial infections can present with centrilobular ground-glass nodules 4
• In TB-endemic regions or high-risk patients, tuberculosis must be excluded first given high prevalence 2
• Ill-defined centrilobular nodules of ground-glass attenuation were seen in all 15 patients with subacute HP in one pathologic correlation study, distinguishing it from the tree-in-bud appearance of infectious bronchiolitis 4

Other Inflammatory Processes

• Respiratory bronchiolitis-associated interstitial lung disease (RBILD) presents with ill-defined centrilobular ground-glass nodules in all cases 4
• Microscopic polyangiitis (27 of 48 patients) and systemic lupus erythematosus (7 of 8 patients) can present similarly 4
• Churg-Strauss syndrome occasionally manifests this pattern (4 of 12 patients) 4

Critical Diagnostic Algorithm

Step 1: Obtain Detailed Exposure History

• Immediately obtain detailed exposure history to birds, mold, hot tubs, feather bedding, or occupational antigens—this dramatically increases diagnostic confidence 2, 3
• Smoking history is essential: HP is highly suggestive in nonsmokers with this pattern 1

Step 2: Perform High-Resolution CT with Expiratory Views

• Expiratory imaging is essential to confirm air trapping in suspected HP, as inspiratory images alone may be indeterminate 3
• Upper/middle lobe predominance + mosaic attenuation strongly favors HP 3
• Extensive ground-glass opacity (>30% lung involvement) without basal predominance suggests HP, NSIP, or organizing pneumonia rather than usual interstitial pneumonia 3

Step 3: Obtain Bronchoalveolar Lavage (BAL)

• BAL with lymphocyte differential >20% supports HP diagnosis 2
• Obtain sputum cultures, acid-fast bacilli smears, and nucleic acid amplification testing for TB simultaneously 2
• Transbronchial biopsy increases diagnostic yield when combined with BAL, particularly in fibrotic HP 2

Step 4: Consider Antigen-Specific Testing (Limited Value)

• There is insufficient evidence to support serum antigen-specific antibody testing to reliably confirm or rule out HP due to cross-reactivity, poorly standardized techniques, and false-negative results 1
• Antigen-specific inhalation challenge testing is not recommended due to limited diagnostic utility and potential adverse effects 1

Immediate Management Based on Leading Diagnosis

If HP is Most Likely

• Immediate and complete antigen avoidance is the cornerstone of treatment for HP 2
• Do not make a clinical diagnosis of HP based on clinical improvement with medical therapy alone 1

If Infection Cannot Be Excluded

• Empiric antibiotics should be initiated immediately for bacterial pneumonia without waiting for culture results 2
• In TB-endemic regions, do not delay TB evaluation in high-risk patients 2

Critical Pitfalls to Avoid

• Do not assume infectious etiology without considering HP, especially in nonsmokers with exposure history 2
• Do not diagnose idiopathic pulmonary fibrosis when centrilobular nodules are present—this finding strongly suggests an alternative diagnosis, most commonly HP 3
• Do not overlook recent medication changes, as drug-related pneumonitis can occur 3-12 weeks after drug initiation 2
• Extensive ground-glass opacity (>30% of lung involvement) argues against idiopathic pulmonary fibrosis and should prompt consideration of alternative diagnoses 2
• In one retrospective study, increased opacification from expiration was incorrectly interpreted as widespread ground-glass opacity in 10.2% of patients—ensure true inspiratory technique 5

Pathologic Correlation

• Ill-defined centrilobular ground-glass nodules pathologically represent peribronchiolar inflammation or deposition of hemorrhagic materials 4
• This contrasts with the tree-in-bud appearance, which correlates with plugging of small airways with mucous, pus, or fluid—a pattern more typical of infectious bronchiolitis 4