What are the causes, symptoms, and management options for a patient with interstitial lung disease (ILD)?

Interstitial Lung Disease: Causes, Symptoms, and Management

Causes of Interstitial Lung Disease

ILD encompasses over 300 distinct etiologies that can be categorized into six main groups: autoimmune/connective tissue disease-associated (CTD-ILD), idiopathic interstitial pneumonias, hypersensitivity pneumonitis, drug-induced, infection-related, and unclassified forms. 1

Primary Etiologic Categories

• Connective tissue disease-associated ILD accounts for approximately 20-25% of all ILD cases, with systemic sclerosis-ILD (31%) and rheumatoid arthritis-ILD (39%) being the most common CTD-ILD subtypes 2, 3
• Other autoimmune causes include idiopathic inflammatory myopathy (dermatomyositis, polymyositis, antisynthetase syndrome), primary Sjögren's syndrome, systemic lupus erythematosus, and mixed connective tissue disease 2
• Idiopathic pulmonary fibrosis (IPF) represents approximately one-third of all ILD cases and is the most common form 3
• Hypersensitivity pneumonitis accounts for 15% of ILD cases, typically from organic antigen exposures including mold 3, 2

Risk Factors and Genetic Predisposition

• Familial pulmonary fibrosis (FPF) is defined by two or more genetically related first- or second-degree relatives with fibrotic ILD, accounting for up to 20% of pulmonary fibrosis cases 2
• The MUC5B promoter variant is strongly associated with ILD development, and first-degree relatives of patients with sporadic IPF have 15-30% prevalence of interstitial lung abnormalities on chest CT 2
• Environmental and occupational exposures including smoking, silica, asbestos, air pollution, and certain medications increase ILD risk 2, 1

Clinical Presentation and Symptoms

The hallmark symptom of ILD is progressive dyspnea on exertion, present in virtually all patients, though early disease may be asymptomatic with irreversible lung function loss occurring before symptoms develop. 2, 3

Cardinal Symptoms

• Dyspnea on exertion is the primary presenting symptom in ILD 3
• Dry cough occurs in approximately 30% of patients with ILD 3
• Fatigue is a common nonspecific symptom that may be attributed to other organ involvement or comorbidities 2

Critical Diagnostic Pitfall

• Early but irreversible lung function loss can occur asymptomatically, making high clinical suspicion essential in at-risk populations 2
• Symptoms may be masked by other organ involvement (myopathy, cardiac disease) or attributed to deconditioning, leading to delayed diagnosis 2
• Maintaining a high level of suspicion for ILD is critical because early recognition can stabilize or slow irreversible lung function loss 2

Diagnostic Approach

A multidisciplinary team approach involving pulmonologists, rheumatologists, radiologists, and pathologists is essential for accurate ILD diagnosis and classification. 2, 4

Initial Evaluation

• High-resolution chest CT (HRCT) is approximately 91% sensitive and 71% specific for diagnosing ILD subtypes such as IPF 3
• Baseline symptom assessment should specifically inquire about cough and dyspnea on exertion 2
• Pulmonary function testing (PFT) including forced vital capacity (FVC), total lung capacity (TLC), and diffusion capacity for carbon monoxide (DLCO) establishes baseline and provides prognostic information 2

Screening Recommendations for High-Risk Populations

• Baseline chest CT screening is suggested for adults with connective tissue diseases associated with increased ILD risk (rheumatoid arthritis, systemic sclerosis, polymyositis, dermatomyositis, antisynthetase syndrome, mixed CTD, Sjögren's disease) 2
• Chest CT screening is suggested for adults ≥50 years with a first-degree relative with familial pulmonary fibrosis 2
• Systematic assessment for ILA/ILD is suggested in smokers undergoing lung cancer screening with chest CT 2

Distinguishing ILA from ILD

• Interstitial lung abnormalities (ILA) are defined as nondependent bilateral parenchymal abnormalities involving ≤5% of a lung zone without meeting criteria for ILD 2
• ILD diagnosis requires either: (1) definite fibrosis (honeycombing and/or reticulation with traction bronchiectasis) involving >5% of total lung volume, OR (2) respiratory symptoms attributable to imaging findings, OR (3) abnormal pulmonary physiology (reduced FVC, TLC, or DLCO) 2

Management Strategies

Management of ILD must be tailored to the specific underlying etiology, with immunosuppressive therapy for CTD-ILD and antifibrotic therapy for IPF and progressive pulmonary fibrosis. 2, 5

Treatment of Connective Tissue Disease-Associated ILD

Mycophenolate is the preferred first-line immunosuppressive therapy across all SARD-ILD subtypes. 2, 5, 6

First-Line Immunosuppressive Options

• Mycophenolate is conditionally recommended as first-line therapy for all SARD-ILD 2, 5
• Rituximab is conditionally recommended as a first-line alternative for SARD-ILD 2, 4
• Cyclophosphamide is conditionally recommended as first-line therapy, typically not combined with other agents 2, 5
• Azathioprine is conditionally recommended for most SARD-ILD except systemic sclerosis 2, 5

Disease-Specific Recommendations

• For systemic sclerosis-ILD: Tocilizumab and nintedanib are conditionally recommended as first-line options 2, 4
• For idiopathic inflammatory myopathy-ILD: JAK inhibitors and calcineurin inhibitors are conditionally recommended as first-line options 2, 4
• Glucocorticoids are conditionally recommended for SARD-ILD other than SSc-ILD, but strongly recommended against for SSc-ILD as first-line treatment 2

Agents to Avoid in SARD-ILD

• Leflunomide, methotrexate, TNF inhibitors, and abatacept are conditionally recommended against as first-line ILD treatment, though they may be appropriate for extrapulmonary manifestations 2, 6

Treatment of Idiopathic Pulmonary Fibrosis

Antifibrotic therapy with either pirfenidone or nintedanib is the standard of care for IPF, slowing annual FVC decline by approximately 44-57%. 5, 3

• Pirfenidone or nintedanib have similar efficacy in slowing disease progression in IPF 5
• Immunosuppressive therapy is not effective and may be harmful in IPF with definite UIP pattern 5
• Pirfenidone is administered at 2,403 mg/day in three divided doses with food 7

Management of Progressive Pulmonary Fibrosis

For patients developing progressive pulmonary fibrosis (PPF) despite initial immunosuppressive therapy, adding nintedanib is conditionally recommended. 5, 4

Defining Progressive Pulmonary Fibrosis

• PPF is defined by ≥10% decline in FVC, worsening respiratory symptoms, and/or radiographic progression within the past year despite treatment 5
• A 5% decline in FVC over 12 months is associated with approximately 2-fold increase in mortality compared with no change in FVC 3

Treatment Options for Progressive Disease

• Mycophenolate, rituximab, cyclophosphamide, and nintedanib are conditionally recommended for SARD-ILD progression despite first-line treatment 2
• For RA-ILD progression: Adding pirfenidone is conditionally recommended 2
• Long-term glucocorticoids are strongly recommended against for SSc-ILD progression and conditionally recommended against for other SARD-ILD progression 2

Management of Rapidly Progressive ILD

• Methylprednisolone pulses and initial combination therapy are recommended as first-line treatment for rapidly progressive ILD 6
• Referral for lung transplantation should be considered early in rapidly progressive disease 6

Non-Pharmacological Management

Structured exercise therapy and pulmonary rehabilitation reduce symptoms and improve 6-minute walk test distance in individuals with dyspnea. 3, 1

• Oxygen therapy reduces symptoms and improves quality of life in individuals who desaturate below 88% on 6-minute walk test 3
• Pulmonary rehabilitation enhances functional capacity and quality of life 1

Lung Transplantation

• Lung transplant should be considered for patients with end-stage ILD, with median survival of 5.2-6.7 years post-transplant compared to less than 2 years without transplant in advanced ILD 3
• For SSc-ILD progression despite first ILD treatment, referral for stem cell transplantation and/or lung transplantation is conditionally recommended 2

Monitoring Strategy

Short-term PFTs and HRCT should be performed to determine rate of progression, with follow-up intervals based on disease severity. 4

• Patients with mild ILD: PFTs every 6 months for the first 1-2 years 4
• Patients with moderate-to-severe ILD or progressive disease: More frequent monitoring is required 4
• Serial monitoring should assess for features indicating increased risk of progression 8

Management of Pulmonary Hypertension

• Up to 85% of individuals with end-stage fibrotic ILD develop pulmonary hypertension 3
• Inhaled treprostinil improves walking distance and respiratory symptoms in these patients 3

Critical Management Principles

Co-management with pulmonologists is essential for initiating ILD treatment, particularly for determining treatment necessity in asymptomatic patients with stable and mild ILD. 6

• Multidisciplinary discussion involving pulmonologists, rheumatologists, radiologists, and pathologists improves diagnostic accuracy and patient outcomes 4
• Cases that are "unclassifiable" often prove to be CTD-related or drug-induced rather than idiopathic on multidisciplinary review 4
• Treatment goals should be based on disease behavior patterns: reversible and self-limited, reversible with risk of progression, stable with residual disease, progressive but potentially stabilizable, or progressive and irreversible despite therapy 4