What is the initial approach to treating Interstitial Lung Disease (ILD)?

Interstitial Lung Disease: Comprehensive Overview

Introduction

Interstitial lung disease (ILD) is a heterogeneous group of parenchymal lung disorders characterized by inflammation and/or fibrosis, affecting approximately 650,000 people in the US with 25,000-30,000 annual deaths, requiring early multidisciplinary recognition to prevent irreversible lung damage. 1

ILD encompasses diverse etiologies with CTD-associated ILD representing 20% of all cases, with SSc-ILD and RA-ILD accounting for 31% and 39% of CTD-ILDs respectively 2. The most common forms include idiopathic pulmonary fibrosis (IPF) at 33%, hypersensitivity pneumonitis at 15%, and connective tissue disease-related ILD at 25% 1.

Clinical Features

Presenting Symptoms

The hallmark presentation is progressive dyspnea on exertion, though early disease may be asymptomatic with irreversible lung function loss occurring before symptom onset. 2

• Dyspnea on exertion is the primary symptom, though symptom assessment alone lacks sensitivity—90% of HRCT-confirmed ILD patients may not report dyspnea or cough 3
• Non-productive cough occurs in approximately 30% of patients 1, 4
• Fatigue is a common but nonspecific symptom that may be masked by other organ involvement or comorbidities (myopathy, cardiac disease) 2

Physical Examination Findings

• Fine inspiratory crackles ("velcro" crackles) on lung auscultation have moderate sensitivity for early ILD identification 3
• Physical findings must be supplemented with comprehensive environmental, occupational, avocational, and medication-use history 5

Critical Pitfall

Maintaining high clinical suspicion is essential as early irreversible lung function loss can occur asymptomatically, and nonspecific symptoms may hide behind other organ involvement 2.

Pathogenesis

ILD pathogenesis involves inflammation and/or progressive fibrosis of lung parenchyma, with a proportion developing progressive pulmonary fibrosis (PPF) causing irreversible damage and increased mortality. 2

• Progressive pulmonary fibrosis represents the primary cause of death in CTD patients alongside cardiovascular comorbidities 2
• Up to 85% of end-stage fibrotic ILD patients develop pulmonary hypertension 1
• The balance between inflammatory and fibrotic processes guides treatment decisions between anti-inflammatory versus anti-fibrotic approaches 3

Diagnosis

Multidisciplinary Team Approach

A multidisciplinary team (MDT) including pulmonologists, radiologists, pathologists, and crucially rheumatologists is the gold standard for ILD diagnosis, improving diagnostic accuracy and patient outcomes. 2, 6

• Adding routine rheumatological assessment can reclassify 21% of presumed IPF as CTD-ILD and increase CTD-ILD with autoimmune features by 77% 6
• Rheumatological evaluation can prevent unnecessary invasive procedures (7 bronchoscopies and 1 surgical biopsy in one study) 6
• MDT collaboration is especially beneficial in complex cases and raises the level of care nationwide 2

Essential MDT Components

The following are essential features for an effective ILD MDM 7:

• At least one radiologist present
• Quiet setting with visual projection system
• High-quality chest HRCT available
• Standardized template summarizing collated patient data

Diagnostic Algorithm

Step 1: Comprehensive History

• Detailed environmental exposure history using systematic standardized questionnaires 4
• Occupational, avocational, and medication-use history—the single most important factor for achieving optimal outcomes 5
• Assessment for CTD symptoms and autoimmune features 6

Step 2: Physical Examination

• Thorough lung auscultation for velcro crackles 3
• Systematic examination for CTD manifestations 6

Step 3: Laboratory Testing

• Autoimmune serologic testing including RF, anti-CCP, ANA, anti-Scl-70, anti-synthetase antibodies, MPO-ANCA 4, 6
• Disease-specific biomarkers to predict disease activity 2

Step 4: Imaging

• High-resolution CT (HRCT) is the gold standard with 91% sensitivity and 71% specificity for diagnosing ILD subtypes 1
• HRCT is not routinely recommended at diagnosis in all CTDs but is essential in patients with suspected ILD 2
• Exception: All SSc patients should undergo HRCT screening at diagnosis regardless of risk factors due to high ILD prevalence 2

Step 5: Functional Assessment

• Complete pulmonary function tests (PFTs) including FVC, TLC, and DLCO 3
• 6-minute walk test (6MWT) to evaluate exercise capacity and oxygen desaturation 3

Step 6: Histopathology (When Needed)

• Avoid unnecessary invasive procedures—HRCT is typically sufficient for diagnosis in most settings 3
• Lung biopsy should not be the primary focus; etiology identification through comprehensive history is more important than precise histologic patterns 5

HRCT Findings

HRCT detects characteristic patterns including ground-glass opacities, reticulation, traction bronchiectasis, and honeycombing that define ILD subtypes. 3

Key Radiologic Patterns

• Ground-glass opacities: Suggest active inflammation
• Reticulation: Indicates interstitial thickening
• Traction bronchiectasis: Reflects fibrotic distortion
• Honeycombing: Represents end-stage fibrosis

Severity Classification

• Mild ILD: FVC ≥70% and <20% fibrosis extent on HRCT 2, 3
• Moderate-to-severe ILD: FVC <70% or ≥20% fibrosis extent on HRCT

PFT Findings

Pulmonary function testing provides crucial prognostic information, with a 5% FVC decline over 12 months associated with approximately 2-fold increased mortality. 1

Baseline Assessment

• FVC (Forced Vital Capacity): Primary marker of restrictive physiology 1
• TLC (Total Lung Capacity): Confirms restriction 3
• DLCO (Diffusion Capacity): Sensitive early marker of ILD 3

Monitoring Schedule

For Mild ILD (FVC ≥70%, <20% fibrosis on HRCT):

• PFTs every 6 months for first 1-2 years 2, 3
• Repeat HRCT within 6 months of initial evaluation 2, 3
• Follow-up HRCT at 2-3 years for stable patients 3

For Moderate-to-Severe or Progressive ILD:

• PFTs every 3-6 months 2, 3
• More frequent HRCT monitoring (within 12 months for concerning cases) 3

Initial Evaluation Timing

• Short-term PFTs within 3 months of diagnosis to determine progression rate 2, 3
• HRCT within 6 months to assess radiological progression 2

Progressive Pulmonary Fibrosis Criteria

PPF is defined by 3:

• Worsening respiratory symptoms, AND
• Physiological evidence of progression on PFTs, AND/OR
• Radiological evidence of progression on chest CT

Biomarkers of ILD

Disease-specific biomarkers predict disease activity and indicate the need for additional testing, though their role is supplementary to clinical, radiologic, and functional assessment. 2

Autoimmune Markers

• Anti-topoisomerase (Scl-70): Associated with SSc-ILD 2
• Rheumatoid factor (RF) and anti-CCP: Predict RA-ILD development 2
• Anti-synthetase antibodies: Define antisynthetase syndrome with ILD 2
• MPO-ANCA: Associated with vasculitis-related ILD 4

Genetic Markers

• MUC5B polymorphism: Risk factor for IPF and other fibrotic ILDs 2

Inflammatory Markers

• ESR (Erythrocyte Sedimentation Rate): Nonspecific marker of disease activity 2

Functional Biomarkers

• 6-minute walk test with oxygen saturation monitoring: Detects exercise-induced desaturation indicating gas exchange impairment 3

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Treatment Approach

Initial Management Strategy

Treatment decisions must integrate the underlying etiology, disease severity, and balance between inflammatory versus fibrotic processes through multidisciplinary consensus. 2, 3

For CTD-Associated ILD:

• First-line: Immunosuppressive agents (mycophenolate mofetil, rituximab, tocilizumab) regardless of fibrosis pattern 2, 1
• Patients evaluated concurrently by pulmonology and rheumatology for integrated disease management 2

For Progressive Pulmonary Fibrosis:

• Antifibrotic therapy (nintedanib or pirfenidone) slows annual FVC decline by 44-57% 1
• Consider for patients showing progression despite initial management 3

For Hypersensitivity Pneumonitis:

• First action: Antigen avoidance when identified 4
• If avoidance fails: Anti-inflammatory drugs (prednisolone) 4

Supportive Care:

• Structured exercise therapy reduces symptoms and improves 6-minute walk distance 1
• Oxygen therapy for patients desaturating below 88% on 6MWT improves symptoms and quality of life 1
• Inhaled treprostinil for pulmonary hypertension in end-stage ILD improves walking distance and symptoms 1

Advanced Disease:

• Lung transplant for end-stage ILD: Median survival 5.2-6.7 years post-transplant versus <2 years without transplant 1