How should interstitial lung disease be evaluated and treated?

Evaluation and Management of Interstitial Lung Disease

For adults with suspected ILD, obtain high-resolution CT (HRCT) as the gold standard diagnostic test, perform comprehensive pulmonary function testing including spirometry with FVC, total lung capacity, and DLCO, and convene a multidisciplinary discussion with pulmonology, radiology, and rheumatology to establish diagnosis and guide treatment. 1, 2

Initial Diagnostic Evaluation

Clinical Assessment

• Assess for dyspnea on exertion and non-productive cough, though recognize that up to 90% of early ILD cases may be asymptomatic 2
• Auscultate for fine, dry "Velcro-type" end-inspiratory crackles, which are present in more than 80% of IPF patients and represent the hallmark physical finding 2, 3
• Examine for digital clubbing, present in 25-50% of IPF patients, though it may be absent in early disease 2
• Document comprehensive environmental and occupational exposure history to identify potential causes of hypersensitivity pneumonitis, including mold, air pollution, and occupational vapors, gases, dusts, and fumes 2
• Obtain detailed family history, as 15-30% of first-degree relatives of patients with familial pulmonary fibrosis exhibit interstitial lung abnormalities 2, 4
• Evaluate for signs and symptoms of connective tissue diseases, which account for 25% of all ILD cases 2, 3

Laboratory Testing

• Order complete blood count with differential, C-reactive protein, comprehensive metabolic panel including serum creatinine, transaminases, gamma-glutamyltransferase, and alkaline phosphatases 2
• Obtain comprehensive autoimmune serology panel including anti-nuclear antibodies, rheumatoid factor, anti-citrullinated cyclic peptide antibodies, anti-synthetase antibodies, anti-Ro/SSA, anti-La/SSB, anti-Scl-70, and anti-centromere antibodies to identify underlying CTD 2, 5
• Do NOT routinely measure serum biomarkers (MMP-7, surfactant protein D, CCL-18, KL-6) for differentiating IPF from other ILDs, as this is not recommended 2

High-Resolution CT Imaging

• Obtain volumetric HRCT with thin sections (≤1.5 mm) on full inspiration, supplemented by prone and expiratory images 2, 5
• HRCT has 95.7% sensitivity and 63.8% specificity for detecting ILD with ≥20% lung involvement, making it far superior to chest radiography, which misses up to 10% of ILD cases 2
• Recognize key HRCT patterns:
  • Usual interstitial pneumonia (UIP): subpleural reticulation, traction bronchiectasis, honeycomb cysts, basal-peripheral distribution 2
  • Non-specific interstitial pneumonia (NSIP): ground-glass opacities with reticulation and more uniform distribution, most common pattern in CTD-ILD (36.5% prevalence) 2, 6
  • Organizing pneumonia: peribronchial consolidation 2
• When HRCT shows definite UIP pattern, do NOT perform surgical lung biopsy, transbronchial biopsy, or cryobiopsy, as tissue diagnosis is not indicated 2

Pulmonary Function Testing

• Measure FVC to identify restrictive pattern (decreased FVC indicates restriction) 2, 3
• Measure total lung capacity (TLC) to confirm restriction 2
• Measure diffusion capacity (DLCO) to assess gas exchange impairment, which is typically reduced in ILD 2, 3
• Perform 6-minute walk test to evaluate exercise capacity and oxygen desaturation 2
• Recognize that baseline FVC <80% has only 47.5% sensitivity for detecting ILD, emphasizing the critical need for HRCT imaging 2
• Define severe disease as FVC <60% predicted or DLCO <40% predicted, which warrants urgent therapeutic consideration 5

Additional Diagnostic Procedures

• Perform echocardiography in all patients to rule out structural cardiovascular disease and pulmonary hypertension, as up to 85% of individuals with end-stage fibrotic ILD develop pulmonary hypertension 1, 2, 3
• Consider flexible bronchoscopy with bronchoalveolar lavage (BAL) when diagnostic uncertainty exists:
  • Lymphocyte count >25% suggests granulomatous diseases (sarcoidosis, hypersensitivity pneumonitis), cellular NSIP, drug-induced lung injury, or cryptogenic organizing pneumonia 2
  • Lymphocyte count >50% strongly points toward hypersensitivity pneumonitis or cellular NSIP 2
  • Eosinophil count >25% is virtually diagnostic of acute or chronic eosinophilic pneumonia 2
  • CD4+/CD8- ratio >4 is highly specific for sarcoidosis 2
• Do NOT perform BAL cellular analysis in patients with UIP pattern on HRCT, as it is not recommended 2

Tissue Diagnosis When Needed

• For patients in whom HRCT and clinical findings are insufficient for definitive diagnosis, consider transbronchial lung cryobiopsy (TBLC) as first-line biopsy method 2
• TBLC provides larger samples without crush artifacts and has lower complication rates than surgical lung biopsy 2
• Reserve surgical lung biopsy for rapidly progressive cases or when TBLC yields nondiagnostic results 2, 5
• For neonates and infants with severe or rapidly progressive disease, test for genetic abnormalities (SFTPB, SFTPC, ABCA3 gene mutations) 1

Mandatory Multidisciplinary Discussion

• Convene multidisciplinary discussion (MDD) involving pulmonologists, radiologists, and pathologists (plus rheumatologists when CTD is suspected) to integrate clinical, radiological, and pathological findings 2, 5, 7
• MDD improves diagnostic accuracy and is mandatory for optimal diagnostic yield 2, 7

Treatment Based on ILD Subtype

Idiopathic Pulmonary Fibrosis (IPF)

• Initiate antifibrotic therapy with nintedanib or pirfenidone at the time of diagnosis, as both agents reduce annual FVC decline by approximately 44-57% and have comparable efficacy 2, 3
• Do NOT use immunosuppressive therapy for IPF, as it is not effective and may be harmful 4
• Refer patients with elevated mortality risk for lung transplant evaluation at the time of diagnosis 2

Connective Tissue Disease-Associated ILD (CTD-ILD)

• For most CTD-ILD patients (except SSc-ILD), initiate mycophenolate mofetil 1-1.5g twice daily as first-line treatment 2, 4, 3
• Alternative first-line options include azathioprine, rituximab, or cyclophosphamide 2
• For systemic sclerosis-ILD (SSc-ILD):
  • Do NOT use glucocorticoids as first-line treatment (strong recommendation against) 2
  • Consider tocilizumab as first-line option 2
  • Consider nintedanib 2
• For rheumatoid arthritis-ILD with UIP pattern or progressive disease, add nintedanib to immunosuppressive therapy 5
• For idiopathic inflammatory myopathy-ILD, consider JAK inhibitors or calcineurin inhibitors 2

Progressive Fibrosing ILD (PF-ILD)

• Define progressive pulmonary fibrosis by at least TWO of the following within 12 months:
  1. Worsening respiratory symptoms
  2. Absolute FVC decline >5% predicted OR absolute DLCO decline >10% predicted
  3. Radiological progression (increased traction bronchiectasis, new ground-glass opacities, new honeycomb cysts, increased extent/thickness of reticular abnormality) 2
• Initiate antifibrotic therapy with nintedanib or pirfenidone for PF-ILD regardless of underlying ILD subtype 2

Sarcoidosis

• For asymptomatic or mild disease, pursue serial observation without pharmacologic therapy 5
• For symptomatic disease with moderate functional or radiologic abnormalities, initiate moderate-dose oral prednisone (≤60 mg daily) 5
• For patients unable to taper steroids, add steroid-sparing agents such as mycophenolate or azathioprine 5
• Avoid prolonged high-dose corticosteroid therapy due to increased adverse-event risk 5

Non-Pharmacologic Interventions

• Prescribe structured pulmonary rehabilitation, which improves 6-minute walk distance and health-related quality of life 2, 3
• Provide supplemental oxygen for patients desaturating <88% during 6-minute walk test, which reduces dyspnea and enhances quality of life 2, 3
• Counsel on smoking cessation using combined pharmacotherapy (nicotine replacement, varenicline, or bupropion) and behavioral support, as this is the single most effective intervention to slow ILD progression 2
• Remove or remediate identified environmental, occupational, or medication triggers 2
• Ensure age-appropriate vaccinations (influenza and pneumococcal) to lower the risk of respiratory infections that can exacerbate ILD 2

Monitoring and Follow-Up Strategy

• Perform serial pulmonary function tests (spirometry and DLCO) every 3-6 months during the first year after diagnosis, then annually if disease remains stable 2, 5
• A 5% decline in FVC over 12 months is associated with approximately 2-fold increase in mortality 3
• Patients with radiologically progressive ILAs experience accelerated lung function decline, with 64-ml annual FVC decline compared to 35-ml decline in those without ILAs 2
• Repeat HRCT at 2-3 years after baseline scan to assess radiologic progression 2
• In patients with high-risk features (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 2, 4
• Perform follow-up HRCT annually for cancer surveillance 2
• Systematically evaluate and treat comorbidities including gastroesophageal reflux disease, obstructive sleep apnea, and lung cancer 2

Management of Acute Exacerbations and Advanced Disease

• Treat acute exacerbations of ILD with systemic corticosteroids 2
• Do NOT routinely use invasive mechanical ventilation for most patients with respiratory failure due to ILD 2
• For patients with end-stage ILD and pulmonary hypertension, consider inhaled treprostinil, which improves walking distance and respiratory symptoms 3
• Lung transplant should be considered for patients with advanced ILD, as median survival after transplant is 5.2-6.7 years compared to less than 2 years without transplant 3

Critical Pitfalls to Avoid

• Do not delay HRCT while awaiting other investigations, as HRCT is the gold standard and should be obtained promptly 5
• Do not dismiss interstitial lung abnormalities as clinically insignificant even in asymptomatic patients, as ILAs are associated with 66% increased risk of death and approximately 10% annual progression to ILD 2, 4
• Do not attribute cough and dyspnea solely to ILD without excluding cardiac disease, asthma, and postnasal drainage 2
• Do not assume calcified mediastinal nodes exclude CTD-ILD; full autoimmune workup remains mandatory 5
• Recognize that more than half of individuals with ILAs experience progression of radiologic findings over 5 years with associated clinical worsening 1, 2

Screening Recommendations for At-Risk Populations

• For adult smokers undergoing lung cancer screening with chest CT, systematically assess and document the presence or absence of ILAs/ILD, as approximately 8% will have findings 1
• For adults with CTDs associated with increased risk of ILD (systemic sclerosis, rheumatoid arthritis, idiopathic inflammatory myopathies, mixed connective tissue disease, Sjögren's syndrome), obtain baseline chest HRCT to screen for ILAs/ILD 1
• For patients with idiopathic inflammatory myopathies, assess anti-MDA5 and anti-synthetase antibodies at baseline, and urgently refer for HRCT if positive 1