In a patient with bilateral lower‑lobe mosaic attenuation, patchy ground‑glass opacities, interstitial septal and subpleural thickening, and pleural fibrosis, what is the most likely diagnosis and what diagnostic steps and management should be pursued?

Hypersensitivity Pneumonitis (Fibrotic HP)

Based on the imaging findings of bilateral lower-lobe mosaic attenuation with ground-glass opacities, interstitial septal thickening, subpleural thickening, and pleural fibrosis—all accompanied by clear signs of small airway disease—hypersensitivity pneumonitis is the most likely diagnosis and should be pursued aggressively with exposure history, serum precipitins, and consideration for multidisciplinary discussion to determine if surgical lung biopsy is needed. 1

Why Hypersensitivity Pneumonitis is Most Likely

The imaging constellation you describe fits the "compatible with HP" pattern from the 2020 ATS/JRS/ALAT guidelines 1:

• Mosaic attenuation = hallmark of small airway disease, which is required for HP diagnosis
• Ground-glass opacities with interstitial septal thickening = fibrotic changes with superimposed inflammation
• Subpleural thickening and pleural fibrosis = variant fibrosis pattern that can occur in HP
• Lower lobe predominance = while HP classically spares lower zones, variant patterns with lower lobe involvement are recognized when accompanied by small airway disease signs 1

The key distinguishing feature here is that mosaic attenuation in the setting of fibrosis strongly predicts non-UIP pathology, particularly HP and connective tissue disease-associated ILD 2. When mosaic attenuation appears in non-fibrotic areas (≥3 lobes), it predicts non-UIP diagnosis in 60.7% of cases, with HP being one of the most common 2.

Critical Diagnostic Steps

1. Detailed Exposure History (Most Important)

• Occupational exposures: Birds (avian proteins), moldy hay, humidifiers, hot tubs, metalworking fluids
• Home environment: Water damage, mold, feather bedding/pillows, humidifiers, air conditioning systems
• Hobbies: Bird keeping, woodworking, farming
• Temporal relationship: Do symptoms improve away from exposure (weekends, vacations)?

2. Serum Precipitins/IgG Antibodies

• Test for specific antigens based on exposure history
• Caveat: Negative precipitins do NOT rule out HP; positive results only indicate exposure, not disease 1

3. Pulmonary Function Tests

• Expect restrictive pattern with reduced DLCO
• Helps assess severity and establish baseline

4. Bronchoalveolar Lavage (BAL)

• Lymphocytosis (>20%, often >30%) supports HP
• CD4/CD8 ratio typically <1 in HP (though not specific)
• Helps exclude infection and malignancy

5. Surgical Lung Biopsy Consideration

• Indicated when diagnosis remains uncertain after non-invasive workup
• Sample both fibrotic AND less-fibrotic areas (critical for identifying centriacinar fibrotic lesions and peribronchiolar metaplasia characteristic of HP) 1
• Multidisciplinary discussion should determine biopsy necessity

Alternative Diagnoses to Consider

Nonspecific Interstitial Pneumonia (NSIP)

• Would show bilateral patchy ground-glass opacities with subpleural predominance 3
• Key difference: NSIP typically lacks mosaic attenuation and small airway disease features
• No honeycombing (consistent with your case) 3
• However, the prominent mosaic attenuation makes this less likely

Connective Tissue Disease-Associated ILD

• Can present identically to HP with mosaic attenuation in non-fibrotic areas 2
• Must screen: ANA, RF, anti-CCP, myositis panel (anti-Jo-1, anti-PL-7, anti-PL-12), anti-Scl-70
• Look for extrapulmonary manifestations: arthralgia, myalgia, Raynaud's, mechanic's hands, skin changes 4

Management Algorithm

Immediate Actions:

1. Remove from suspected exposure if identified (most critical intervention)
2. Corticosteroids: Prednisone 0.5-1 mg/kg/day for 4-12 weeks, then taper
3. Antifibrotic therapy: Consider nintedanib or pirfenidone if significant fibrosis present (as in your case with pleural fibrosis) 1

If Fibrotic HP Confirmed:

• Prognosis is worse with established fibrosis 1
• Aggressive immunosuppression: Add mycophenolate mofetil or azathioprine if inadequate response to steroids alone
• Antifibrotic agents should be strongly considered given the fibrotic changes already present
• Serial PFTs every 3-6 months to monitor progression

Critical Pitfalls to Avoid

1. Don't dismiss HP because of lower lobe involvement: Variant patterns with lower lobe fibrosis are recognized when small airway disease is present 1

2. Don't rely solely on precipitins: Sensitivity is poor; negative results don't exclude HP 1

3. Don't biopsy only fibrotic areas: Sample less-fibrotic lung to identify characteristic HP features; one site may look like UIP while another shows typical HP 1

4. Don't overlook connective tissue disease: The imaging overlap is substantial; screen for autoimmune markers, especially if no clear exposure identified 2, 4

5. Don't confuse mosaic attenuation etiology: Assess vessel caliber in lucent areas (small = airway/vascular disease) and obtain expiratory images to confirm air trapping 5, 6, 7

The presence of mosaic attenuation + ground-glass opacities + septal thickening + fibrosis creates a pattern most consistent with fibrotic HP with ongoing small airway involvement, requiring urgent exposure identification and combined anti-inflammatory/antifibrotic therapy to prevent further irreversible lung damage.