What are the steps to diagnose fibrotic lung disease?

Diagnostic Approach to Fibrotic Lung Disease

Begin with a detailed occupational, environmental, and medication exposure history combined with serological testing for connective tissue disease, followed by high-resolution computed tomography (HRCT) as the gold standard imaging modality, and reserve tissue biopsy for cases where clinical and radiologic features are discordant or indeterminate. 1

Initial Clinical Assessment

History Taking (Mandatory First Step)

• Document all medication exposures including prescription drugs, over-the-counter medications, and supplements that could cause drug-induced lung toxicity 1
• Obtain comprehensive environmental exposure history covering home, workplace, and frequently visited locations to identify potential inhaled organic antigens (hypersensitivity pneumonitis) or mineral particles (pneumoconiosis) 1, 2
• Assess for connective tissue disease symptoms including joint pain, skin changes, Raynaud's phenomenon, dry eyes/mouth, and muscle weakness 1, 3
• Evaluate temporal relationship between any identified exposures and symptom onset, as this strongly suggests hypersensitivity pneumonitis over idiopathic pulmonary fibrosis 4

Clinical Features That Guide Diagnosis

• Male sex, age >60 years, and cigarette smoking history strongly favor idiopathic pulmonary fibrosis (IPF), with likelihood increasing when these features combine 1, 4
• Bibasilar inspiratory crackles (Velcro-type) are present in >80% of IPF cases and appear early in disease 1, 3
• Inspiratory squeaks on auscultation suggest fibrotic hypersensitivity pneumonitis over IPF 4
• Digital clubbing occurs in 25-50% of IPF patients but may be absent in early disease 3
• Absence of fever is typical for IPF; persistent fever should prompt consideration of infection, hypersensitivity pneumonitis, connective tissue disease-ILD, or malignancy 5

Mandatory Serological Testing

Perform serological testing to exclude connective tissue diseases as the cause (motherhood statement from ATS/ERS/JRS/ALAT guidelines) 1:

• Anti-nuclear antibodies (ANA)
• Rheumatoid factor
• Anti-citrullinated cyclic peptide antibodies
• Additional autoimmune serologies based on clinical suspicion 3

High-Resolution Computed Tomography (HRCT)

HRCT is the gold standard for diagnosing fibrotic lung disease and must be performed in all suspected cases. 1, 3

Technical Requirements

• Volumetric acquisition at sustained end-inspiration in supine position 1
• End-expiratory images (volumetric or sequential) to detect air trapping 1
• Prone inspiratory views if dependent atelectasis obscures findings 1
• Thin collimation (≤2 mm slice thickness) with appropriate radiation dose reduction protocols 1

HRCT Pattern Classification (2018 ATS/ERS/JRS/ALAT Criteria)

The 2018 guidelines refined HRCT patterns into four categories that directly determine subsequent diagnostic steps 1:

1. UIP Pattern (Definite)

• Subpleural and basal predominant distribution
• Honeycombing with or without peripheral traction bronchiectasis/bronchiolectasis
• May have mild ground-glass opacities 1

2. Probable UIP Pattern

• Subpleural and basal predominant distribution
• Reticular pattern with peripheral traction bronchiectasis/bronchiolectasis
• Lacks honeycombing (key distinction from definite UIP)
• May have mild ground-glass opacities 1

3. Indeterminate for UIP Pattern

• Features of fibrosis that don't meet UIP or probable UIP criteria
• Includes cases with very limited subpleural ground-glass opacification or reticulation without obvious fibrosis (confirm with prone views to exclude dependent atelectasis) 1

4. Alternative Diagnosis Pattern

• Features suggesting specific alternative diagnoses:
  • Cysts, marked mosaic attenuation, predominant ground-glass opacities
  • Profuse micronodules, centrilobular nodules, consolidation
  • Peribronchovascular or perilymphatic distribution
  • Upper or mid-lung predominance
  • Ancillary findings: pleural plaques (asbestosis), dilated esophagus (connective tissue disease), distal clavicular erosions (rheumatoid arthritis) 1

Radiologic Features Distinguishing IPF from Fibrotic Hypersensitivity Pneumonitis

• Small airways abnormalities with fibrosis (mosaic attenuation, centrilobular nodules, air trapping) suggest fibrotic hypersensitivity pneumonitis 4
• Basal and subpleural-predominant reticulation with honeycombing defines definite UIP pattern associated with IPF 4

Diagnostic Algorithm Based on HRCT Pattern

For HRCT Pattern of UIP (Definite):

Strong recommendations AGAINST invasive procedures 1:

• Do NOT perform surgical lung biopsy (strong recommendation) 1
• Do NOT perform transbronchial lung biopsy (strong recommendation) 1
• Do NOT perform lung cryobiopsy (strong recommendation) 1
• Suggest NOT performing BAL cellular analysis (conditional recommendation) 1

Rationale: The UIP pattern on HRCT in the appropriate clinical context (after excluding other causes) is sufficient for IPF diagnosis without tissue confirmation 1

For HRCT Patterns of Probable UIP, Indeterminate for UIP, or Alternative Diagnosis:

Conditional recommendations FOR additional diagnostic procedures 1:

Bronchoalveolar Lavage (BAL)

• Suggest performing BAL cellular analysis (conditional recommendation) 1
• BAL lymphocytosis >30% strongly suggests fibrotic hypersensitivity pneumonitis, though sensitivity decreases in established fibrosis 4
• BAL can help exclude alternative diagnoses (eosinophilia, malignancy, infection) 3

Surgical Lung Biopsy (SLB)

• Suggest performing surgical lung biopsy (conditional recommendation) 1
• Obtain biopsies from 2-3 different lobes because histologic patterns can be discordant between segments 1
• Do NOT perform SLB in high-risk patients: severe hypoxemia at rest, severe pulmonary hypertension, or DLCO <25% after correction for hematocrit 1

Transbronchial Lung Cryobiopsy (TBLC)

• No formal recommendation for or against in 2018 ATS/ERS/JRS/ALAT guidelines 1
• Consider TBLC as first-line biopsy method when histopathological confirmation is needed, as it provides larger samples without crush artifacts and has lower complication rates than SLB 3

Conventional Transbronchial Biopsy

• No formal recommendation for or against in 2018 guidelines 1
• Diagnostic yield is only 36.1% with adequate samples obtained in 77.6% of cases 1

Multidisciplinary Discussion (MDD)

Multidisciplinary discussion is conditionally recommended for diagnostic decision-making and is mandatory for optimal diagnostic yield in complex cases 1, 3.

MDD Composition and Process

• Include pulmonologists, radiologists, and pathologists (when tissue is available) 1, 3
• Integrate clinical profile, radiologic pattern, and pathologic findings (if available) to generate a leading diagnosis with confidence level 1
• Assign relative weights to each domain during discussion, with moderate-to-high confidence (≥70%) serving as the threshold for confident diagnosis 1
• Patients with clear and concordant clinical and radiologic features may not require full MDD to secure diagnosis 1

When MDD is Essential

• Discordant clinical and radiologic features 1
• Indeterminate findings in at least one diagnostic domain 1
• Younger patients (<50 years) with suspected IPF who may have subclinical connective tissue disease or familial pulmonary fibrosis 1
• Cases where histopathology shows UIP pattern with mild peribronchiolar or granulomatous features difficult to classify 1

Biomarkers

Do NOT measure serum MMP-7, surfactant protein D, CCL-18, or KL-6 for the sole purpose of distinguishing IPF from other interstitial lung diseases (strong recommendation) 1.

Pulmonary Function Testing

While not diagnostic alone, perform the following to assess severity and guide prognosis 1, 3:

• Spirometry to identify restrictive pattern (decreased FVC)
• Total lung capacity (TLC) to confirm restriction
• Diffusion capacity (DLCO) to assess gas exchange impairment
• 6-minute walk test to evaluate exercise capacity and oxygen desaturation

Note: Baseline FVC <80% has only 47.5% sensitivity for detecting ILD, emphasizing the primacy of HRCT imaging 3

Common Pitfalls to Avoid

• Do not rely on chest radiography alone: up to 10% of ILD patients have normal chest X-rays 3
• Do not attribute symptoms solely to ILD without excluding cardiac disease, asthma, and postnasal drainage 3
• Do not perform SLB in patients with definite UIP pattern on HRCT in appropriate clinical context—this exposes patients to unnecessary surgical risk 1
• Do not overlook familial pulmonary fibrosis in younger patients or those with atypical presentations 1
• Confirm subpleural opacities with prone views to exclude dependent atelectasis before classifying as indeterminate pattern 1