What is the systematic step‑by‑step work‑up for a patient with suspected interstitial lung disease?

Systematic Work-Up for Suspected Interstitial Lung Disease

The diagnostic work-up for suspected ILD requires a structured, stepwise approach integrating clinical assessment, high-resolution CT imaging, pulmonary function testing, and targeted laboratory evaluation, culminating in multidisciplinary discussion to establish a definitive diagnosis. 1

Step 1: Clinical History and Physical Examination

History Taking

• Document respiratory symptoms: Assess for dyspnea on exertion and non-productive cough, though recognize that up to 90% of early ILD cases may be asymptomatic 1
• Obtain detailed exposure history: Systematically document environmental exposures (mold, air pollution), occupational exposures (vapors, gases, dusts, fumes), and medication history, as these interact with genetic susceptibility to drive disease development 1
• Assess for connective tissue disease features: Screen for symptoms of rheumatoid arthritis, systemic sclerosis, polymyositis, dermatomyositis, antisynthetase syndrome, mixed CTD, and Sjögren's disease, as CTD accounts for 25% of ILD cases 1, 2
• Elicit family history: Document any family history of pulmonary fibrosis, as 15-30% of first-degree relatives of patients with familial pulmonary fibrosis have interstitial lung abnormalities on CT 1
• Record smoking history: Current or former smoking is present in the majority of IPF patients and represents a major risk factor 1

Physical Examination

• Auscultate for fine "Velcro" crackles: These end-inspiratory crackles are present in >80% of IPF patients and are the hallmark finding, initially most prevalent in lung bases and extending toward upper zones with progression 1, 2
• Examine for digital clubbing: Present in 25-50% of IPF patients, though may be absent in early disease 1
• Assess for cyanosis and weight loss: Cyanosis appears in late-stage disease indicating severe gas exchange impairment; fever is rare and suggests alternative diagnosis 1
• Evaluate for signs of pulmonary hypertension: Check for right ventricular heave, accentuated pulmonic second sound, and peripheral edema in advanced disease 1

Step 2: High-Resolution Computed Tomography (HRCT)

HRCT is the gold standard for ILD diagnosis and must be performed in all patients with suspected ILD. 1

Technical Specifications

• Acquire volumetric HRCT on full inspiration with 1.5 mm slice thickness 2
• Obtain additional acquisitions in ventral decubitus and on expiration (1 mm slice thickness, 20 mm interval) at baseline 2
• HRCT has 95.7% sensitivity and 63.8% specificity for detecting ILD with ≥20% lung involvement 1

Pattern Recognition

• Usual Interstitial Pneumonia (UIP) pattern: Subpleural reticulation, traction bronchiectasis, honeycombing, basal-peripheral distribution 1
• Nonspecific Interstitial Pneumonia (NSIP) pattern: Ground-glass opacities with reticulation and more uniform distribution 1
• Early fibrotic changes: Fine reticulation, intralobular lines, architectural distortion 1

Critical decision point: When HRCT shows a definite UIP pattern in the appropriate clinical context, surgical lung biopsy, transbronchial biopsy, or cryobiopsy is NOT indicated 1

Step 3: Pulmonary Function Testing

Baseline PFTs are essential to establish a baseline for future comparison and identify early ILD. 1

Required Tests

• Spirometry: Measure forced vital capacity (FVC) to identify restrictive pattern; note that baseline FVC <80% has only 47.5% sensitivity for detecting ILD 1
• Total lung capacity (TLC): Confirms restrictive physiology 1
• Diffusing capacity (DLCO): Assesses gas exchange impairment and is often the earliest physiologic abnormality in ILD 1, 2
• 6-minute walk test: Evaluates exercise capacity and oxygen desaturation 1

Step 4: Laboratory Testing

Basic Laboratory Panel

• Complete blood count with differential 1, 3
• C-reactive protein (CRP) to evaluate inflammatory activity 3
• Serum creatinine, transaminases, γ-glutamyltransferase, and alkaline phosphatases to evaluate organ function 1, 3

Autoimmune Serological Testing

Comprehensive autoimmune panel is mandatory to investigate underlying CTD, as CTD accounts for 25% of ILD cases. 1

• Antinuclear antibodies (ANA) by immunofluorescence: Positive ANA significantly increases likelihood of CTD diagnosis (OR=14.4 when titer >1/320) 3
• Rheumatoid factor (RF) and anti-cyclic citrullinated peptide (anti-CCP): High specificity for RA-ILD 3
• Anti-Scl-70/topoisomerase-1: For suspected systemic sclerosis, associated with increased ILD risk 3
• Myositis-specific antibodies: Including anti-synthetase antibodies (Jo-1 and others), strongly associated with ILD in inflammatory myopathies 3
• Anti-SSA/Ro and anti-SSB/La: For suspected Sjögren's syndrome 3

Critical pitfall to avoid: Do not rely solely on negative serologies to rule out CTD-ILD, as some patients may not initially meet standard rheumatologic diagnostic criteria; consider repeat testing if clinical suspicion remains high 3

Biomarkers NOT Recommended

• Do NOT routinely measure serum biomarkers (MMP-7, surfactant protein D, CCL-18, KL-6) for differentiating IPF from other ILDs 1
• Do NOT perform MUC5B testing or telomere length measurement as initial tests even in patients with family history of pulmonary fibrosis 2

Step 5: Cardiovascular Evaluation

• Routine echocardiography is strongly recommended in the initial work-up to identify structural cardiac or vascular anomalies and detect pulmonary hypertension, which is associated with worse prognosis 1

Step 6: Bronchoalveolar Lavage (BAL) - Selective Use

BAL is generally reserved for cases where the first diagnostic impression is inconclusive, or when infection or lung toxicity is suspected. 2

Diagnostic Thresholds When BAL is Performed

• Lymphocyte count >25%: Suggests granulomatous diseases (sarcoidosis, hypersensitivity pneumonitis, chronic beryllium disease), cellular NSIP, drug-induced lung injury, or cryptogenic organizing pneumonia 1
• Lymphocyte count >50%: Strongly points toward hypersensitivity pneumonitis or cellular NSIP 1
• Eosinophil count >25%: Virtually diagnostic of acute or chronic eosinophilic pneumonia 1
• CD4+/CD8- ratio >4: Highly specific for sarcoidosis when other inflammatory cell populations are not markedly increased 1

Critical decision point: BAL cellular analysis is NOT recommended in patients with a UIP pattern on HRCT 1

Step 7: Tissue Diagnosis - When Indicated

When HRCT and clinical findings are insufficient for definitive diagnosis, consider lung biopsy. 4

Biopsy Approach

• Transbronchial lung cryobiopsy (TBLC) is suggested as first-line biopsy method for patients who need histopathological confirmation, as it provides larger samples without crush artifacts and has lower complication rates than surgical lung biopsy 1
• Surgical lung biopsy should be considered in rapidly progressive ILD cases or when TBLC yields nondiagnostic results 1
• In cryobiopsy series, unclassifiable cases increase to 17.2% versus 1.3% in VATS biopsy due to smaller tissue samples 4

Step 8: Multidisciplinary Discussion (MDD)

MDD involving pulmonologists, radiologists, and pathologists is mandatory for optimal diagnostic yield and increases diagnostic accuracy. 1, 2

MDD Framework

• Integrate clinical, radiological, and pathological findings to establish a final diagnosis 1
• Classify patients into four tiers: Confident diagnosis (>90% certainty), provisional diagnosis with high confidence (70-90%), provisional diagnosis with low confidence (50-70%), or unclassifiable ILD (<50% certainty) 4
• The concept of working diagnosis can be revised upon additional information, especially longitudinal disease behavior, helping deal with diagnostic uncertainty 5

Step 9: Risk Stratification and Follow-Up Planning

Initial Follow-Up Schedule

• Serial PFTs every 3-6 months during the first year after diagnosis, then annually if stable 1
• Repeat HRCT at 2-3 years after baseline scan to assess radiologic progression 1
• In high-risk patients (definite fibrosis, subpleural fibrotic pattern, extensive radiographic abnormalities, abnormal PFTs, family history of fibrosis, older age, or smoking history), perform earlier HRCT at 12 months 1

Risk Reduction Interventions

• Smoking cessation using combined pharmacotherapy (nicotine replacement, varenicline, or bupropion) and behavioral support 1
• Removal or remediation of identified environmental, occupational, or medication triggers 1
• Age-appropriate vaccinations (influenza and pneumococcal) to lower risk of respiratory infections 1

Common Pitfalls to Avoid

• Do not dismiss findings as clinically insignificant in asymptomatic patients: ILAs are associated with 66% increased risk of death and progression risk regardless of symptoms 1
• Do not attribute cough and dyspnea solely to ILD: Exclude cardiac disease, asthma, and postnasal drainage 1
• Do not rely solely on chest radiography: Up to 10% of ILD patients have normal chest X-rays 1
• Do not delay referral to multidisciplinary team: This can lead to misdiagnosis and inappropriate treatment 2
• Do not fail to repeat serological testing: Some autoantibodies may develop over time 3