What blood tests should be ordered to evaluate a patient with suspected pulmonary fibrosis?

Blood Investigation for Pulmonary Fibrosis

All patients with suspected pulmonary fibrosis must undergo serological testing to exclude connective tissue disease and other identifiable causes before any diagnosis can be established. 1

Mandatory First-Tier Laboratory Panel

Order these tests in every patient with suspected pulmonary fibrosis:

• Complete blood count with differential to detect cytopenias, anemia, or abnormal cell populations indicating systemic inflammation or autoimmune disease 1
• C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR) as inflammatory markers, though recognize that approximately 20% of patients with active connective tissue disease may have normal values 1, 2
• Antinuclear antibodies (ANA) by immunofluorescence as the essential screening test—positive in 10-20% of ILD patients and critical because connective tissue disease accounts for 25% of all ILD cases 1, 2, 3
• Rheumatoid factor (RF) and anti-cyclic citrullinated peptide (anti-CCP) antibodies to evaluate for rheumatoid arthritis-associated ILD 1
• Serum creatinine, transaminases, gamma-glutamyltransferase, and alkaline phosphatases to assess organ function and identify extrapulmonary involvement 1

Second-Tier Testing Based on Clinical Clues or Positive ANA

If the patient has Raynaud's phenomenon, skin changes, or sclerodactyly, immediately add:

• Anti-Scl-70/topoisomerase-1, anti-centromere, anti-RNA polymerase III, and anti-U3RNP antibodies for systemic sclerosis 1, 2

If the patient reports dry eyes, dry mouth, or sicca symptoms, add:

• Anti-SSA/Ro and anti-SSB/La antibodies for Sjögren syndrome 1, 2

If the patient has muscle weakness, myalgias, or elevated CRP, add:

• Creatine phosphokinase (CPK), myoglobin, aldolase, and anti-synthetase antibodies (including anti-Jo-1) for inflammatory myopathy 1, 2

If vasculitis is suspected based on systemic symptoms, add:

• Anti-neutrophil cytoplasmic antibodies (ANCA) 1, 2

Additional Screening Tests

• Serum protein electrophoresis if lymphoproliferative disorder is suspected based on clinical presentation 1, 2
• Anti-thyroid antibodies depending on clinical picture 1, 2
• Hepatitis B, hepatitis C, and HIV serologies to exclude these as associated diagnoses or confounding factors, and because these are required before initiating immunosuppressive therapy 2

Critical Diagnostic Pitfalls to Avoid

Never label a case as idiopathic pulmonary fibrosis without first excluding connective tissue disease, even when serologies are only mildly abnormal or systemic features are subtle, because pulmonary involvement can precede overt connective tissue disease by years and represents the first manifestation in many cases. 1, 4 The majority of panelists refer patients to rheumatology only when positive clinical manifestations, serologies, or atypical features emerge (e.g., female sex, age <60 years). 1

Do not dismiss connective tissue disease based on normal inflammatory markers alone—approximately 20% of patients with active disease have normal CRP/ESR. 2

Algorithmic Approach

1. Start with the mandatory first-tier panel in all patients 1
2. If ANA is positive or any extrapulmonary symptoms exist, proceed immediately to targeted second-tier testing based on the specific clinical features 1, 2
3. If hypersensitivity pneumonitis is suspected based on exposure history, add precipitin testing for organic antigens 1
4. Coordinate blood work with high-resolution CT (≤1.5 mm slices) to establish pattern classification, as the combination of serological and radiological findings drives the multidisciplinary discussion 4

Strength of Evidence

The recommendation for routine serological testing is a "motherhood statement" from the 2018 ATS/ERS/JRS/ALAT guideline, reflecting overwhelming consensus that foregoing serological testing is not a reasonable alternative. 1 The French practical guidelines provide the most detailed tiered approach to specific antibody testing. 1