What are the risk factors, diagnostic approach, and treatment options for a patient with interstitial lung disease (ILD)?

Interstitial Lung Disease: Risk Factors, Diagnosis, and Treatment

Risk Factors

The most critical risk factors for ILD include connective tissue diseases (accounting for 25% of cases), smoking history combined with genetic susceptibility (particularly MUC5B promoter variant), family history of pulmonary fibrosis, and occupational/environmental exposures. 1, 2

Connective Tissue Disease-Associated Risk Factors

• Systemic sclerosis and rheumatoid arthritis are the most common CTD associations, representing 31% and 39% of CTD-ILD cases respectively 3
• Idiopathic inflammatory myopathies with anti-MDA5 and anti-synthetase antibodies require urgent assessment due to risk of rapidly progressive ILD 1
• Systemic lupus erythematosus risk factors include male gender, older age, previous acute lupus pneumonitis, Raynaud phenomenon, gastroesophageal reflux disease, and anti-Sm/anti-U1-RNP seropositivity 1
• Sjögren syndrome patients with specific autoantibody profiles warrant closer monitoring 1

Genetic and Familial Risk Factors

• First-degree relatives of patients with familial pulmonary fibrosis or sporadic IPF have 15-30% prevalence of interstitial lung abnormalities on chest CT 1
• MUC5B promoter variant substantially increases risk, particularly in individuals >50 years of age 1
• Reduced peripheral blood leukocyte telomere length is associated with increased ILD risk 1

Environmental and Occupational Exposures

• Smoking history is a major causative driver, with approximately 8% of smokers undergoing lung cancer screening having ILAs/ILD 4
• Mold exposure and air pollution interact with genetic susceptibility as causative drivers 1
• Occupational exposures require detailed systematic questionnaires to identify potential antigens in hypersensitivity pneumonitis 5

Diagnostic Approach

High-resolution computed tomography (HRCT) is the gold standard for ILD diagnosis with 91% sensitivity and 71% specificity, and must be combined with pulmonary function testing and multidisciplinary discussion for optimal diagnostic accuracy. 3, 2

Initial Clinical Assessment

• Evaluate for dyspnea on exertion as the primary symptom, though 90% of HRCT-confirmed ILD patients may be asymptomatic early in disease 4, 3
• Auscultate for fine, dry "Velcro-type" end-inspiratory crackles at lung bases, present in >80% of IPF patients 4
• Assess for digital clubbing, present in 25-50% of IPF patients, though may be absent in early disease 4
• Document chronic non-productive cough, occurring in 30.5% of patients with ILAs versus 13.9% without 4
• Examine for signs of connective tissue disease including skin changes, joint involvement, muscle weakness, and Raynaud phenomenon 1

Laboratory Testing

• Complete blood count with differential, C-reactive protein, serum creatinine, and liver function tests should be performed at baseline 4
• Autoimmune serologies including anti-nuclear antibodies, rheumatoid factor, anti-CCP antibodies, anti-Scl-70, anti-La/SSB, and anti-U1RNP should be tested 1, 6
• Myositis-specific antibodies (anti-MDA5, anti-synthetase) must be evaluated in suspected inflammatory myopathy 1, 6
• Do not routinely order MUC5B testing or telomere length measurement as initial tests even with family history of pulmonary fibrosis 6

Imaging Studies

• HRCT with volumetric acquisition on full inspiration (1.5 mm slice thickness) is mandatory for all patients with suspected ILD 1, 6
• Additional acquisitions in prone position and on expiration (1 mm slice thickness, 20 mm interval) should be performed at baseline 6
• Identify specific patterns: usual interstitial pneumonia (UIP)/probable UIP, fibrotic hypersensitivity pneumonitis, fibrotic NSIP, ground-glass opacities, reticular abnormalities, traction bronchiectasis, and honeycombing 1, 6
• Chest radiography alone is insufficient as up to 10% of ILD patients have normal chest X-rays 4

Pulmonary Function Testing

• Spirometry to measure forced vital capacity (FVC) is essential, though baseline FVC <80% has only 47.5% sensitivity for detecting ILD 4, 6
• Total lung capacity (TLC) measurement confirms restrictive pattern 4, 6
• Diffusing capacity for carbon monoxide (DLCO) is often the earliest physiologic abnormality, with DLCO <80% showing 83.6% sensitivity for ILD detection 4, 6, 7
• Six-minute walk test with oxygen saturation monitoring detects exercise-induced desaturation indicating gas exchange impairment 4, 3
• Maximal inspiratory and expiratory pressures should be measured in idiopathic inflammatory myopathy patients 1

Tissue Diagnosis When Needed

• Transbronchial lung cryobiopsy (TBLC) is first-line when histopathological confirmation is needed, providing larger samples without crush artifacts and lower complication rates than surgical lung biopsy 4
• Bronchoalveolar lavage (BAL) is reserved for cases where initial diagnosis is inconclusive or when infection/lung toxicity is suspected, with lymphocyte count >25% suggesting granulomatous disease or cellular NSIP 4, 6
• Surgical lung biopsy should be considered when diagnosis remains uncertain after non-invasive testing 6

Multidisciplinary Discussion

• Mandatory integration of clinical, radiological, and pathological findings by pulmonologists, radiologists, and pathologists improves diagnostic accuracy 1, 4, 3, 6
• Classify the specific ILD pattern including UIP, NSIP, hypersensitivity pneumonitis, or CTD-specific patterns 6

Disease-Specific Screening Algorithms

For Idiopathic Inflammatory Myopathies:

• All patients require baseline clinical examination, chest radiograph, PFTs (spirometry, DLCO, respiratory pressures), and autoantibody profile 1
• Urgent HRCT for patients with anti-MDA5 or anti-synthetase antibodies at baseline 1
• High-risk patients need annual PFTs and chest radiograph, with repeat HRCT if symptoms or PFT abnormalities appear 1

For Systemic Lupus Erythematosus:

• Baseline PFTs and chest radiography for all patients 1
• Annual PFTs for high-risk patients (male gender, older age, anti-Sm/anti-U1RNP positive) 1
• HRCT only if symptoms or PFT abnormalities develop 1

For First-Degree Relatives of Familial Pulmonary Fibrosis:

• Chest CT screening recommended for adults ≥50 years of age 6

Treatment

For idiopathic pulmonary fibrosis and progressive pulmonary fibrosis, antifibrotic therapy with nintedanib or pirfenidone slows annual FVC decline by 44-57%; for CTD-ILD, immunosuppressive agents (mycophenolate, rituximab, tocilizumab) are first-line regardless of fibrosis pattern. 3, 8, 2

Antifibrotic Therapy for IPF and Progressive Pulmonary Fibrosis

• Pirfenidone 2,403 mg/day (801 mg three times daily with food) reduces mean FVC decline compared to placebo (mean treatment difference 193 mL at Week 52) 8
• Nintedanib is an alternative antifibrotic agent with similar efficacy 3, 2
• Both agents slow FVC decline by approximately 44-57% in IPF, scleroderma-associated ILD, and progressive pulmonary fibrosis of any cause 2

Immunomodulatory Therapy for CTD-ILD

• For most CTD-ILD patients (except SSc-ILD), consider mycophenolate, azathioprine, rituximab, or cyclophosphamide as first-line treatment 4
• Avoid glucocorticoids as first-line treatment in SSc-ILD (strong recommendation against) 4
• Tocilizumab is conditionally recommended as first-line for SSc-ILD and mixed connective tissue disease-ILD 4
• Nintedanib is conditionally recommended for SSc-ILD 4
• JAK inhibitors and calcineurin inhibitors are conditionally recommended for idiopathic inflammatory myopathy-ILD 4
• Mycophenolate mofetil, rituximab, and tocilizumab may slow decline or improve FVC at 12-month follow-up 2

Hypersensitivity Pneumonitis Management

• Antigen avoidance is the first action when causative antigen is identified or suspected 5
• If antigen avoidance does not improve clinical status, introduce prednisolone 5

Supportive Care

• Structured exercise therapy reduces symptoms and improves 6-minute walk test distance in individuals with dyspnea 2
• Oxygen therapy reduces symptoms and improves quality of life in individuals who desaturate below 88% on 6-minute walk test 2
• Inhaled treprostinil improves walking distance and respiratory symptoms in patients with pulmonary hypertension (present in up to 85% of end-stage fibrotic ILD) 2

Lung Transplantation

• Consider lung transplant for patients with end-stage ILD, as median survival post-transplant is 5.2-6.7 years compared to <2 years without transplant in advanced ILD 2

Monitoring and Follow-Up

Serial PFTs at 3-6 month intervals initially, then annually if stable, combined with symptom assessment and follow-up HRCT based on clinical changes, are essential for detecting progressive pulmonary fibrosis. 4, 6

Monitoring Parameters

• Serial pulmonary function tests (spirometry and DLCO) at 3-6 month intervals initially, then annually if stable 4, 6
• A 5% FVC decline over 12 months is associated with approximately 2-fold increased mortality 3, 2
• Follow-up HRCT at intervals determined by underlying diagnosis and clinical stability, typically within 12-24 months from baseline for stable CTD patients 6
• Regular clinical assessment for symptom progression including dyspnea, cough, and exercise tolerance 4
• Ambulatory desaturation testing every 3-12 months 4

Definition of Progressive Pulmonary Fibrosis

Progressive pulmonary fibrosis is defined by at least two of the following within the past year: 4

• Worsening respiratory symptoms
• Physiological evidence of progression on PFTs (≥10% relative decline in FVC or ≥15% relative decline in DLCO)
• Radiological evidence of progression on chest CT

Critical Pitfalls to Avoid

• Do not dismiss interstitial lung abnormalities as clinically insignificant in asymptomatic patients, as ILAs are associated with 66% increased risk of death and progression to ILD in approximately 10% annually 4
• Do not attribute cough and dyspnea solely to ILD without excluding cardiac disease, asthma, and postnasal drainage 4
• Do not rely solely on pulmonary function tests for diagnosis, as they lack specificity for differential diagnosis and baseline FVC <80% has only 47.5% sensitivity 4, 6
• Do not delay referral to multidisciplinary team, as this leads to misdiagnosis and inappropriate treatment 6
• Do not overlook connective tissue disease in patients presenting with interstitial changes, as CTD accounts for 25% of ILD cases 4, 2
• Do not fail to distinguish between interstitial lung abnormalities (ILAs) and established ILD, as management differs significantly 6