Interstitial Lung Disease vs Pulmonary Fibrosis: Diagnostic and Management Distinctions
Understanding the Relationship
Interstitial lung disease (ILD) is a broad umbrella term encompassing over 200 different pulmonary disorders characterized by inflammation and/or fibrosis of the lung parenchyma, while pulmonary fibrosis represents a specific pathologic endpoint that can occur in many forms of ILD. 1, 2 Pulmonary fibrosis is not a separate entity from ILD—it is a manifestation or consequence of certain ILDs, particularly idiopathic pulmonary fibrosis (IPF), which represents the most common progressive fibrotic ILD. 2
Key Conceptual Framework
ILD encompasses both inflammatory and fibrotic lung diseases, including those with known causes (hypersensitivity pneumonitis, connective tissue disease-associated ILD, drug-induced ILD) and unknown causes (idiopathic interstitial pneumonias including IPF, NSIP, COP). 1, 3
Pulmonary fibrosis specifically refers to scarring and architectural distortion of the lung parenchyma with abnormal extracellular matrix deposition, which can be the predominant feature in certain ILDs or develop as a consequence of chronic inflammation in others. 1, 2
IPF accounts for approximately one-third of all ILD cases and is defined by the presence of usual interstitial pneumonia (UIP) pattern on HRCT and/or surgical lung biopsy in the absence of identifiable causes. 2, 1
Diagnostic Approach: Distinguishing ILD Subtypes
Initial Clinical Assessment
Obtain detailed exposure history to identify hypersensitivity pneumonitis (organic antigens, mold), pneumoconiosis (silica, asbestos), or drug-induced ILD, as these account for over 80% of identifiable causes. 1, 3, 4
Screen systematically for connective tissue diseases, which account for 25% of ILD cases, including rheumatoid arthritis, systemic sclerosis, polymyositis/dermatomyositis, Sjögren's syndrome, and mixed connective tissue disease. 1, 2
Assess for characteristic symptoms: progressive exertional dyspnea (present in 37% with ILD vs 18% without), chronic cough (30% of ILD patients), and fine bibasilar inspiratory "Velcro" crackles (present in >80% of IPF cases). 5, 2
Document digital clubbing (present in 25-50% of IPF patients), though its absence does not exclude fibrotic ILD. 5
Essential Laboratory Evaluation
Complete autoimmune serologic panel: anti-nuclear antibodies, rheumatoid factor, anti-CCP antibodies, anti-SSA/SSB (Sjögren's), anti-topoisomerase-1 and anti-centromere (systemic sclerosis), anti-synthetase antibodies, and myositis panel. 1, 5
Obtain serum precipitins when hypersensitivity pneumonitis is suspected based on exposure history or HRCT findings. 6
Baseline laboratory assessment: CBC with differential, C-reactive protein, serum creatinine, transaminases, gamma-glutamyltransferase, and alkaline phosphatases. 1
High-Resolution Computed Tomography (HRCT)
HRCT is the gold standard imaging modality with 91% sensitivity and 71% specificity for diagnosing ILD subtypes and is mandatory in all suspected cases. 5, 2
HRCT Pattern Recognition for IPF/UIP
Definite UIP pattern (all four features required): subpleural basal predominance, reticular abnormality, honeycombing with or without traction bronchiectasis, and absence of features inconsistent with UIP. 1
Possible UIP pattern: subpleural basal predominance, reticular abnormality, absence of features inconsistent with UIP, but lacking honeycombing. 1
Inconsistent with UIP pattern (any one feature): upper or mid-lung predominance, extensive ground-glass abnormality (greater than reticular abnormality), profuse micronodules (bilateral, predominantly upper lobes), or consolidation in bronchopulmonary segments/lobes. 1
Critical Diagnostic Pitfall
The presence or absence of honeycombing on HRCT is central to IPF diagnosis, yet HRCT diagnostic recommendations are not implemented uniformly by most radiologists, leading to frequent misdiagnosis. 1 Patients with peripheral basal reticular changes without honeycombing represent a common diagnostic challenge requiring additional evaluation. 1
Pulmonary Function Testing
Spirometry with FVC and DLCO establishes baseline lung function and disease severity, though baseline FVC <80% has only 47.5% sensitivity for detecting ILD. 1, 5
Total lung capacity (TLC) confirms restrictive physiology when spirometry suggests restriction. 5
A 5% decline in FVC over 12 months is associated with approximately 2-fold increase in mortality compared with stable FVC. 2
Six-minute walk test with oxygen saturation monitoring: oxygen saturation ≤88% at end of test predicts worse prognosis. 7, 2
Bronchoalveolar Lavage (BAL)
BAL cellular analysis should be reserved for cases where the diagnosis remains uncertain after clinical assessment and HRCT, primarily to increase suspicion for alternative diagnoses. 1
Lymphocyte differential count >25% suggests granulomatous disease (sarcoidosis, hypersensitivity pneumonitis, chronic beryllium disease), cellular NSIP, drug reaction, lymphoid interstitial pneumonia, or cryptogenic organizing pneumonia. 1
Lymphocytosis >30% argues against IPF and supports chronic hypersensitivity pneumonitis or NSIP. 1, 6
CD4+/CD8+ ratio >4 is highly specific for sarcoidosis in the absence of increased proportion of other inflammatory cells. 1
Do not perform BAL when HRCT features are classical for IPF and clinical context is appropriate, as the patient has definite IPF. 1
Tissue Diagnosis
When HRCT and clinical findings are insufficient for definitive diagnosis, transbronchial lung cryobiopsy (TBLC) is suggested as first-line biopsy method, providing larger samples without crush artifacts and lower complication rates than surgical lung biopsy. 5
Surgical lung biopsy (SLB) should be performed when patients present with nondiagnostic HRCT scans (possible UIP, indeterminate for UIP, or inconsistent with UIP pattern) and the diagnosis of definite IPF is uncertain. 1, 7
Avoid SLB if DLCO <25% after correction for hematocrit, severe hypoxemia at rest, or severe pulmonary hypertension due to high surgical risk. 7
Do NOT perform SLB if HRCT shows definite UIP pattern, as diagnosis can be made confidently with clinical and radiographic features alone. 7
Multidisciplinary Discussion (MDD)
All cases should undergo multidisciplinary discussion involving pulmonologists, radiologists, and pathologists experienced in ILD to integrate clinical, radiological, and pathological findings, as this approach improves diagnostic accuracy. 1, 5, 7
Management: Tailored to Specific ILD Subtype
Idiopathic Pulmonary Fibrosis (IPF)
Antifibrotic therapy with nintedanib or pirfenidone is first-line treatment, slowing annual FVC decline by approximately 44% to 57%. 8, 2
Do NOT initiate triple therapy with prednisone, azathioprine, and N-acetylcysteine in patients with definite IPF. 7
Do NOT use antacid medication for the purpose of improving respiratory outcomes in IPF, though it may be appropriate for GERD symptoms. 7
Avoid long-term corticosteroids and oral anticoagulants in IPF management. 6
Connective Tissue Disease-Associated ILD
For most CTD-ILD patients (except SSc-ILD), consider mycophenolate, azathioprine, rituximab, or cyclophosphamide as first-line treatment options. 5, 2
Avoid glucocorticoids as first-line treatment in SSc-ILD (strong recommendation against). 5
Tocilizumab is conditionally recommended as first-line option for SSc-ILD and mixed connective tissue disease-ILD. 5
Nintedanib is conditionally recommended for SSc-ILD. 5
JAK inhibitors and calcineurin inhibitors are conditionally recommended for idiopathic inflammatory myopathy-ILD. 5
Progressive Pulmonary Fibrosis (PPF)
Progressive pulmonary fibrosis is defined by at least two of the following within the past year: worsening respiratory symptoms, physiological evidence of progression (≥10% decline in FVC or ≥15% decline in DLCO over 6 months), and radiological evidence of PPF on chest CT. 1, 5, 7
- Antifibrotic therapy with nintedanib or pirfenidone slows FVC decline in progressive pulmonary fibrosis of any cause. 2
Hypersensitivity Pneumonitis
Antigen avoidance is paramount, with consideration of antifibrotics for HP with UIP pattern. 6
Supportive and Advanced Therapies
Structured exercise therapy reduces symptoms and improves 6-minute walk test distance in individuals with dyspnea. 2
Supplemental oxygen reduces symptoms and improves quality of life in individuals who desaturate below 88% on 6-minute walk test. 2
Lung transplant should be considered for patients with advanced ILD, with median survival of 5.2 to 6.7 years post-transplant compared with less than 2 years in advanced ILD without transplant. 2
Inhaled treprostinil improves walking distance and respiratory symptoms in patients with pulmonary hypertension complicating fibrotic ILD (present in up to 85% of end-stage cases). 2
Monitoring Strategy
Repeat PFTs every 3-6 months initially to detect progression, then annually if stable. 5, 7
Follow-up HRCT based on clinical and PFT changes. 5
Assess prognosis using GAP (gender, age, physiology) score for 1-, 2-, and 3-year survival estimates. 7
Critical Pitfalls to Avoid
Do not assume UIP pattern equals IPF without systematically excluding secondary causes including CTD, hypersensitivity pneumonitis, drug-induced ILD, and occupational exposures. 1, 6
Do not dismiss the possibility of CTD-ILD based solely on absence of extrapulmonary manifestations, as ILD may be the first clinical manifestation. 1, 6
Do not overlook elevated IgE in a patient with UIP pattern, as this is inconsistent with typical IPF and should prompt investigation for chronic hypersensitivity pneumonitis or other alternative diagnoses. 6
Do not attribute cough and dyspnea solely to ILD without excluding cardiac disease, asthma, and postnasal drainage. 5
Do not dismiss interstitial lung abnormalities as clinically insignificant even in asymptomatic patients, as they are associated with 66% increased risk of death and progression risk regardless of symptoms. 5