What blood tests are used to investigate Interstitial Lung Disease (ILD)?

Blood Tests for Investigating Interstitial Lung Disease (ILD)

The diagnosis of interstitial lung disease requires a comprehensive autoimmune panel to investigate potential underlying connective tissue diseases (CTDs), as these are common causes of ILD and impact treatment decisions.

Initial Blood Tests for ILD Evaluation

• Complete blood count with differential - to assess for inflammatory markers and rule out other causes 1
• C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR) - to evaluate inflammatory activity 1
• Serum creatinine, transaminases, γ-glutamyltransferase, and alkaline phosphatases - to assess organ function and rule out other causes 1

Autoimmune Serological Testing

Core Autoimmune Panel

• Antinuclear antibodies (ANA) by immunofluorescence - positive ANA significantly increases likelihood of CTD diagnosis (OR=14.4 when titer >1/320) 1, 2
• Rheumatoid factor (RF) - particularly important in suspected RA-ILD 1
• Anti-cyclic citrullinated peptide (anti-CCP) - high specificity for RA-ILD 1

Extended Autoimmune Testing Based on Clinical Suspicion

For suspected systemic sclerosis:

• Anti-Scl-70/topoisomerase-1 - associated with increased ILD risk 1
• Anti-centromere antibodies - considered protective against ILD development 1
• Anti-RNA polymerase III, anti-U1RNP, anti-Th/To, anti-PMScl, U3 RNP (fibrillarin), anti-Ku 1

For suspected inflammatory myopathies:

• Myositis-specific antibodies including:
  • Anti-synthetase antibodies (Jo-1 and others) - strongly associated with ILD 1, 3
  • Anti-MDA5 (melanoma differentiation-associated protein 5) - associated with rapidly progressive ILD 1
  • Anti-Mi-2, anti-NXP2, anti-TIF1-γ, anti-SRP, anti-HMGCR, anti-SAE 1
• Creatine phosphokinase, myoglobin, and aldolase - muscle enzymes 1

For suspected Sjögren's syndrome:

• Anti-SSA/Ro and anti-SSB/La antibodies 1

For suspected vasculitis:

• Anti-neutrophil cytoplasmic antibodies (ANCA) - particularly MPO-ANCA for vasculitis with ILD 1, 4

Biomarkers for Disease Severity and Progression

• Krebs von den Lungen-6 (KL-6) - expressed by damaged alveolar type II cells, useful for:

  • Differentiating fibrotic from non-fibrotic ILD 5
  • Predicting disease progression 5, 3
  • Monitoring treatment response 5

• Neutrophil-to-lymphocyte ratio (NLR) - elevated in progressive pulmonary fibrosis 3

• Lactate dehydrogenase (LDH) - elevated in more severe and progressive ILD 3

Clinical Pearls and Pitfalls

• Pitfall: Relying solely on negative serologies to rule out CTD-ILD. Some patients with CTD-ILD may not initially meet standard rheumatologic diagnostic criteria, termed "interstitial pneumonia with autoimmune features" 1

• Pitfall: Failing to repeat serological testing. Some autoantibodies may develop over time, so consider repeat testing if clinical suspicion remains high despite initial negative results 1

• Pearl: ANA titer matters - titers higher than 1/320 are strongly predictive of CTD diagnosis (OR=14.4) 2

• Pearl: Autoantibody profile can predict ILD progression risk - non-Jo-1 antisynthetase antibodies are associated with higher risk of progressive pulmonary fibrosis compared to Jo-1 antibodies 3

• Pearl: The presence of 'velcro' crackles on lung auscultation should prompt thorough serological evaluation even if respiratory symptoms are minimal 1