What is the likely diagnosis and recommended initial work‑up and management for a 57‑year‑old man with calcified mediastinal lymph nodes, prior axillary lymphadenopathy, and new interstitial lung disease on high‑resolution CT?

Likely Diagnosis and Initial Management

The most likely diagnosis is connective tissue disease-associated interstitial lung disease (CTD-ILD), with sarcoidosis as an important differential given the calcified lymph nodes, and the initial work-up must include comprehensive autoimmune serologies, high-resolution CT pattern analysis, pulmonary function testing, and multidisciplinary discussion to guide treatment decisions. 1

Differential Diagnosis Considerations

Calcified Lymph Nodes: Key Diagnostic Clue

The presence of calcified mediastinal lymph nodes combined with axillary lymphadenopathy strongly suggests sarcoidosis as a primary consideration:

• Sarcoidosis develops lymph node calcification in 20-53% of patients, typically appearing during the second or third decade after disease onset 2, 3
• Calcification patterns differ between diseases: focal/punctate calcification is more common in sarcoidosis (58% of nodes), while complete nodal calcification suggests tuberculosis (62% of nodes) 4
• Bilateral hilar calcification occurs in 65% of sarcoidosis cases versus only 8% in tuberculosis 4
• The 3-year interval between lymphadenopathy and ILD development fits the natural history of sarcoidosis 2, 3

CTD-ILD Remains Critical to Exclude

Despite the calcified nodes suggesting sarcoidosis, CTD-ILD must be systematically excluded because:

• CTD accounts for 25% of all ILD cases and can present with minimal extrapulmonary manifestations 5
• Rheumatoid arthritis-ILD (RA-ILD) is particularly relevant in males >50 years with disease activity 1
• The risk of subclinical RA-ILD in males >58 years with high disease activity reaches 87.2% 1

Initial Diagnostic Work-Up

Immediate Imaging Assessment

Obtain volumetric HRCT with thin-section protocol (≤1.5 mm slice thickness) on full inspiration, with additional prone and expiratory images 1, 6:

• Look for NSIP pattern (bilateral ground-glass opacities with subpleural sparing, irregular reticulation with traction bronchiectasis) versus UIP pattern (subpleural and basal predominant reticulation, honeycombing, traction bronchiectasis) 6, 7
• Document the extent of fibrosis as percentage of total lung volume, as this determines eligibility for antifibrotic therapy 1
• Assess for features suggesting sarcoidosis: perilymphatic nodules, upper lobe predominance, or organizing pneumonia pattern 1
• HRCT interpretation must occur through multidisciplinary discussion with an experienced thoracic radiologist 1, 6

Comprehensive Laboratory Evaluation

Perform complete autoimmune serological panel 1, 8:

• Anti-nuclear antibodies (ANA), rheumatoid factor (RF), anti-CCP antibodies
• Anti-synthetase antibodies (Jo-1, PL-7, PL-12), anti-Ro/SSA, anti-La/SSB
• Anti-topoisomerase (Scl-70), anti-centromere antibodies
• Myositis panel including creatine phosphokinase
• Serum angiotensin-converting enzyme (ACE) and soluble IL-2 receptor for sarcoidosis 3

Obtain baseline inflammatory markers and organ function 1, 8:

• Complete blood count with differential, C-reactive protein, ESR
• Comprehensive metabolic panel including liver function tests
• Serum protein electrophoresis if hypergammaglobulinemia suspected

Pulmonary Function Testing

Perform complete PFTs including spirometry, lung volumes, and DLCO to establish baseline severity 6, 8:

• FVC <60% predicted or DLCO <40% predicted indicates severe disease requiring urgent treatment consideration 1
• A 5% decline in FVC over 6 months predicts 2-fold increased mortality 5

Conduct 6-minute walk test with continuous oxygen saturation monitoring 6, 8:

• SpO2 ≤88% at end of test indicates severe disease and worse prognosis 6, 7

Exposure and Clinical History

Document detailed occupational and environmental exposures to identify hypersensitivity pneumonitis, which accounts for 15% of ILD and was found in 47% of patients initially thought to have ILD of unknown cause 6, 8, 5

Screen systematically for extrapulmonary CTD manifestations 1, 8:

• Arthralgias, morning stiffness, Raynaud's phenomenon
• Skin changes (sclerodactyly, mechanic's hands, heliotrope rash)
• Sicca symptoms (dry eyes, dry mouth)
• Muscle weakness, dysphagia

Bronchoscopy Considerations

Perform bronchoalveolar lavage (BAL) when diagnosis remains uncertain after HRCT and serologies 8:

• Lymphocytosis >25% suggests hypersensitivity pneumonitis or sarcoidosis 8
• CD4/CD8 ratio >3.5 supports sarcoidosis diagnosis
• Neutrophilia or eosinophilia suggests alternative diagnoses 8

Transbronchial biopsy or endobronchial ultrasound-guided biopsy of calcified lymph nodes may confirm sarcoidosis with non-caseating granulomas 3

Multidisciplinary Discussion

All cases must undergo multidisciplinary discussion (MDD) involving pulmonologists, radiologists, and rheumatologists experienced in ILD to integrate clinical, radiological, and laboratory features before treatment decisions 1, 6, 8

Surgical Lung Biopsy Decision Algorithm

Do NOT perform surgical lung biopsy if 6:

• HRCT shows definite UIP pattern (diagnosis can be made confidently without biopsy)
• DLCO <25% after correction for hematocrit
• Severe hypoxemia at rest or severe pulmonary hypertension

Consider surgical lung biopsy if 6, 8:

• HRCT shows probable UIP, indeterminate for UIP, or alternative diagnosis pattern
• Patient is not at high surgical risk
• Diagnosis remains uncertain after comprehensive non-invasive evaluation

Initial Management Strategy

If CTD-ILD is Diagnosed

Initiate mycophenolate mofetil 1000-1500 mg twice daily as first-line therapy for NSIP pattern CTD-ILD 7:

• Monitor complete blood count with differential every 2-4 months 7
• Avoid prolonged high-dose corticosteroids due to adverse effects 1, 7

For RA-ILD with UIP pattern or progressive disease 1:

• Add nintedanib (antifibrotic approved for progressive fibrosing ILD) 1, 5
• Nintedanib slows annual FVC decline by 44-57% 5

If Sarcoidosis is Diagnosed

Treatment depends on disease severity and progression 1:

• Asymptomatic or mild disease: Serial observation without therapy
• Symptomatic with moderate PFT/HRCT abnormalities: Moderate-dose oral corticosteroids (not exceeding 60 mg daily prednisone) 1
• Steroid-sparing agents (mycophenolate or azathioprine) for patients unable to taper corticosteroids 1

Monitoring Protocol

Repeat PFTs every 3-6 months, especially in the first 1-2 years 1, 6:

• ≥10% decline in FVC or ≥15% decline in DLCO over 6 months indicates significant progression requiring treatment escalation 7

Follow-up HRCT within 12 months for stable patients 7:

• Earlier HRCT if clinical deterioration or significant functional decline occurs 7

Critical Pitfalls to Avoid

• Do NOT delay HRCT while pursuing other testing—it is the gold standard for ILD diagnosis and must be obtained immediately 1, 6
• Do NOT assume calcified nodes exclude CTD-ILD—comprehensive autoimmune evaluation is mandatory regardless of lymph node appearance 1, 8
• Do NOT initiate triple therapy (prednisone, azathioprine, N-acetylcysteine) if IPF is diagnosed, as this increases mortality 6
• Do NOT rely on chest radiography alone—it has 91% sensitivity but only 71% specificity compared to HRCT 5, 9
• Do NOT wait for scheduled follow-up if functional decline occurs—immediate reassessment is required 7