What is the likely diagnosis for an adult patient with chronic chest discomfort and lung pain, no cardiac issues, and abnormal results on High-Resolution Computed Tomography (HRCT), Pulmonary Function Tests (PFT), and Diffusing Capacity of the Lung for Carbon Monoxide (DLCO)?

Differential Diagnosis for Chronic Chest Discomfort with Abnormal HRCT, PFT, and DLCO

Based on the clinical presentation of chronic chest/lung symptoms with abnormal HRCT, PFT, and DLCO findings in a patient without cardiac issues or corticosteroid use, you should prioritize screening for connective tissue disease-associated interstitial lung disease (CTD-ILD), with particular focus on systemic sclerosis, rheumatoid arthritis, Sjögren syndrome, mixed connective tissue disease, idiopathic inflammatory myopathies, and systemic lupus erythematosus. 1, 2

Primary Diagnostic Considerations

Connective Tissue Disease-Associated ILD (CTD-ILD)

The combination of abnormal HRCT and reduced DLCO is highly suggestive of CTD-ILD, which accounts for nearly 20% of all ILDs in Europe and the USA. 2 The American College of Rheumatology specifically recommends suspecting autoimmune ILD when evaluating patients with these findings. 1, 2

Specific CTD Entities to Assess:

Systemic Sclerosis (SSc):

• Nearly 50% of SSc patients develop ILD, accounting for approximately 31% of all CTD-ILD cases 2
• HRCT and PFTs (spirometry and DLCO) should be performed at baseline 1
• Look for Raynaud's phenomenon, skin thickening, esophageal dysfunction, and anti-Scl-70 antibodies 1, 2

Rheumatoid Arthritis (RA):

• Accounts for approximately 39% of CTD-ILD cases 2
• 61% of RA patients may have asymptomatic ILD detectable on HRCT 3
• Screen for joint symptoms, rheumatoid factor, and anti-CCP antibodies 1

Sjögren Syndrome (SS):

• ILD occurs in 9-30% of SS patients 1
• Associated with fourfold increased risk of 10-year mortality 1
• Risk factors include male sex, age ≥65 years, anti-SSB/La, anti-Ro52 antibodies, elevated CRP 1
• Baseline PFTs (spirometry and DLCO) and chest radiography should be performed in all SS patients 1

Mixed Connective Tissue Disease (MCTD):

• All MCTD patients should undergo HRCT and PFTs at diagnosis 1, 4
• Risk factors include esophageal dysfunction, dysphagia, Raynaud's phenomenon, anti-Smith or anti-Ro-52 antibodies 1, 4
• High anti-ribonucleoprotein antibody titers predict ILD progression 1

Idiopathic Inflammatory Myopathies (IIM):

• Clinical presentation, autoantibody profile (anti-MDA5, anti-synthetase), chest radiograph, and PFTs with DLCO should be assessed at baseline 1
• Urgent assessment necessary for patients with anti-MDA5 and anti-synthetase antibodies 1

Systemic Lupus Erythematosus (SLE):

• ILD occurs in 1-15% of SLE patients 1
• Risk factors include anti-La/SSB, anti-Scl-70, anti-U1RNP antibodies, Raynaud phenomenon, elevated CRP 1
• Symptomatic patients should undergo PFTs (spirometry and DLCO) and HRCT 1

Idiopathic Pulmonary Fibrosis (IPF)

If autoimmune workup is negative, consider IPF, particularly if HRCT shows reticular abnormalities with or without honeycombing. 5

• Reduced DLCO combined with reticular abnormalities supports IPF diagnosis even without definitive honeycombing 5
• DLCO >30% lymphocytosis on BAL suggests alternative diagnoses like hypersensitivity pneumonitis or NSIP rather than IPF 5

Diagnostic Algorithm

Step 1: Initial Screening Tests

Perform comprehensive autoimmune serologic panel: 2

• Antinuclear antibody (ANA)
• Rheumatoid factor and anti-CCP antibodies
• Anti-Scl-70, anti-centromere antibodies
• Anti-SSA/Ro, anti-SSB/La, anti-Ro52 antibodies
• Anti-Smith, anti-U1RNP antibodies
• Anti-synthetase antibodies (Jo-1, PL-7, PL-12)
• Anti-MDA5 antibodies
• Inflammatory markers (ESR, CRP)

Step 2: Detailed Clinical Assessment

Evaluate for specific CTD manifestations: 2

• Raynaud's phenomenon (common in MCTD and SSc) 1, 2
• Skin changes (SSc)
• Joint symptoms (RA, SLE)
• Dry eyes/mouth (SS)
• Muscle weakness (IIM)
• Esophageal dysfunction (MCTD, SSc) 1

Step 3: Imaging Interpretation

HRCT has 95.7% sensitivity and 63.8% specificity for detecting ILD ≥20% extent: 2

• Ground glass opacities suggest NSIP pattern (most common in SS-ILD) 1
• Reticulation with traction bronchiectasis suggests fibrotic ILD 6
• UIP pattern may indicate RA-ILD or IPF 1
• Lymphoid interstitial pneumonia pattern suggests SS 1

Step 4: Functional Assessment

The combination of reduced DLCO <80%, abnormal chest X-ray, and pulmonary HRCT yields 95.2% sensitivity and 77.4% specificity for detecting ILD: 6

• DLCO and TLC are the most predictive parameters for CTD-ILD severity 7
• FVC <80% alone has only 63% sensitivity for ILD detection 8
• The combination of FVC <80% or DLCO <80% improves sensitivity to 85% 8

Critical Pitfalls to Avoid

Do not rely on PFTs alone for ILD screening: 8

• PFTs have inadequate sensitivity, particularly in early disease 8
• 57 of 63 RA-ILD patients in one study lacked significant dyspnea or cough at diagnosis 3
• HRCT should be part of the screening algorithm, not reserved for symptomatic patients 1, 8

Do not dismiss nonspecific symptoms: 2

• Early but irreversible organ damage can occur asymptomatically 2
• Progressive dyspnea >6 months is the most prominent symptom when ILD develops 2
• "Velcro" crackles have only 69% sensitivity and 66% specificity 2

Do not delay autoimmune workup: 2

• Nearly 20% of ILDs are associated with autoimmune rheumatic diseases 2
• In cases of interstitial pneumonia without known CTD, perform autoimmune panel to investigate underlying CTD 2
• Negative autoantibodies do not exclude disease progression, especially early in disease course 2

Do not use arbitrary fixed percentages for PFT interpretation: 5

• Use lower limit of normal (5th percentile) when possible 5
• DLCO and TLC reductions are more predictive than FVC alone 7