What is the appropriate management for a patient presenting with interstitial opacities, potentially indicative of interstitial lung disease (ILD) or idiopathic pulmonary fibrosis (IPF)?

Management of Interstitial Opacities

The immediate priority when encountering interstitial opacities is obtaining high-resolution computed tomography (HRCT) with specific technical parameters to characterize the pattern, followed by systematic exclusion of secondary causes before considering idiopathic interstitial lung disease. 1

Initial Diagnostic Workup

HRCT Technical Requirements

The diagnostic evaluation begins with proper HRCT imaging using mandatory technical specifications: 1

• No contrast medium administration 1
• Slice thickness ≤2 mm with inspiratory breath-hold 1
• Axial contiguous or non-contiguous slices separated by ≤2 cm 1
• Volumetric acquisition with thin sections (≤1.5 mm) at full inspiration for baseline studies 1, 2
• Prone positioning images if gravity-dependent opacities obscure analysis in supine position 1
• Expiratory slices to exclude lobular air trapping, particularly when hypersensitivity pneumonitis is suspected 1

Pattern Recognition on HRCT

The HRCT pattern determines the diagnostic pathway and has direct implications for prognosis and treatment: 1

UIP Pattern (suggests IPF): 1

• Subpleural and basal predominant distribution with heterogeneous appearance
• Honeycombing with or without traction bronchiectasis/bronchiolectasis (definitive feature)
• Areas of normal lung interspersed with fibrosis
• May have mild ground-glass opacity superimposed

Probable UIP Pattern: 1

• Subpleural and basal predominant reticular pattern
• Traction bronchiectasis or bronchiolectasis present
• May have mild ground-glass opacity
• Absence of honeycombing

Indeterminate for UIP: 1

• Features of fibrosis that don't meet UIP or probable UIP criteria
• Doesn't explicitly suggest alternative diagnosis
• Includes very limited subpleural ground-glass opacification or reticulation without obvious fibrosis features
• Requires prone inspiratory views to exclude dependent atelectasis

Alternative Diagnosis Patterns: 1

• Predominant ground-glass opacity with subpleural sparing suggests NSIP 1, 3
• Profuse mosaic attenuation or centrilobular nodules suggest hypersensitivity pneumonitis 1
• Peribronchovascular predominance with subpleural sparing suggests NSIP 1
• Upper or mid-lung predominance suggests alternative diagnosis 1
• Consolidation suggests organizing pneumonia 1

Mandatory Exclusion of Secondary Causes

Before diagnosing idiopathic disease, systematically exclude: 1

Connective tissue disease: 1

• Complete autoimmune panel: ANA, rheumatoid factor, anti-CCP, anti-Scl-70, anti-Jo-1, myositis panel, ANCA 4
• High ANA titers (>1:160) suggest CTD rather than IPF and require immunosuppression 4
• Look for dilated esophagus on HRCT (suggests CTD) 1
• Distal clavicular erosions suggest rheumatoid arthritis 1

Hypersensitivity pneumonitis: 1, 4

• Detailed antigen exposure history (birds, mold, hot tubs, occupational exposures) 4
• Consider antigen avoidance trial 4
• Bronchoalveolar lavage with >20% lymphocytes supports HP diagnosis 4

Drug-induced ILD: 1

• Review all medications, particularly mesalamine, sulfasalazine, methotrexate, amiodarone, nitrofurantoin 5
• If drug-induced ILD suspected, discontinue offending agent immediately 5

Occupational exposures: 1

• Pleural plaques on HRCT suggest asbestosis 1

Lung Biopsy Indications and Technique

Biopsy is indicated when HRCT features are insufficient to diagnose IPF (i.e., indeterminate for UIP pattern or alternative diagnosis pattern without clear etiology). 1

Biopsy Technical Requirements: 1

• Video-assisted surgical lung biopsy (VATS) is preferred over transbronchial biopsy 1
• Sample from multiple lobes (2-3 lobes) in depth, avoiding lingula and middle lobe extremities 1
• Perform in surgical centers experienced in ILD management 1
• Balance biopsy risk against patient age, comorbidities, and diagnostic uncertainty through multidisciplinary discussion 1

Histopathologic Patterns: 1

UIP pattern: 1

• Patchy dense fibrosis causing architectural remodeling
• Honeycombing with alternating areas of less-affected parenchyma
• Subpleural and paraseptal predominance
• Fibroblast foci present
• Temporally heterogeneous

Probable UIP pattern: 1

• Features suggestive but not definitive for UIP

NSIP pattern: 1, 3

• Temporally uniform inflammation or fibrosis (key distinguishing feature from UIP) 1
• Bilateral ground-glass opacities predominant 2, 3
• Irregular reticular opacities with traction bronchiectasis in ~75% 2
• Subpleural sparing helps distinguish from UIP 2
• Honeycomb areas rare 1

Diagnosis Integration: HRCT + Histopathology

The 2022 ATS/ERS/JRS/ALAT guideline provides an algorithmic approach: 1

• UIP pattern on HRCT = IPF diagnosis (no biopsy needed) 1
• Probable UIP on HRCT + UIP on biopsy = IPF diagnosis 1
• Probable UIP on HRCT + Probable UIP on biopsy = IPF diagnosis 1
• Indeterminate HRCT + UIP on biopsy = IPF diagnosis 1
• Indeterminate HRCT + Probable UIP on biopsy = IPF likely (especially with moderate-severe traction bronchiectasis in ≥4 lobes in men >50 or women >60) 1

Treatment Based on Final Diagnosis

For Confirmed IPF (UIP Pattern):

Antifibrotic therapy is first-line: 6, 7, 8

• Pirfenidone 2,403 mg/day (801 mg three times daily with food) OR nintedanib 6, 7
• These agents slow annual FVC decline by 44-57% 7
• Pirfenidone reduced mean FVC decline from -428 mL to -235 mL at 52 weeks (193 mL treatment difference) 6

Avoid harmful therapies: 1

• Do NOT initiate triple therapy with prednisone + azathioprine + N-acetylcysteine (increased mortality and hospitalization risk) 1
• NAC monotherapy may be considered only if approved antifibrotic drugs are not indicated, after considering clinical trial participation 1

For NSIP Pattern:

Immunosuppression is first-line: 2, 5, 7

• Mycophenolate 1000-1500 mg twice daily is preferred first-line therapy 2, 4
• Monitor CBC with differential every 2-4 months 2
• Rituximab is conditionally recommended alternative 2, 4
• Corticosteroids result in improvement in most patients 1, 5
• Estimated 15-20% mortality at 5 years (much better than IPF) 1, 5

For Progressive Fibrotic ILD (any cause):

Consider adding antifibrotic therapy: 2, 7

• Nintedanib or pirfenidone for progressive disease despite immunosuppression 2
• Particularly when predominant fibrotic features present 2

Prognostic Assessment

Poor Prognostic Factors in IPF: 1

• Older age and male sex 1
• Severe dyspnea at presentation 1
• DLCO ≤35-40% predicted 1
• Oxygen saturation ≤88% during 6-minute walk test 1
• Extensive honeycombing on HRCT 1

GAP Score for Survival Prediction: 1

• Use GAP (Gender, Age, Physiology) score based on age, sex, FVC, and DLCO to predict 1-, 2-, and 3-year survival 1

Surveillance Protocol

Pulmonary Function Testing: 1, 2, 7

• Obtain PFTs every 3-6 months 2, 7
• ≥10% relative or ≥5% absolute FVC decline over 6 months indicates significant progression 1, 2
• ≥15% DLCO decline over 6 months indicates significant progression 1, 2
• ≥50 m decrease in 6-minute walk distance indicates progression 1
• 5% FVC decline over 12 months associated with ~2-fold increase in mortality 7

HRCT Surveillance: 2

• Follow-up HRCT within 12 months for clinically and functionally stable patients 2
• Obtain earlier HRCT if clinical symptoms worsen or significant functional decline occurs 2
• Worsening fibrosis on HRCT indicates poor prognosis 1

Supportive Care

Oxygen Therapy: 7

• Prescribe supplemental oxygen for patients who desaturate below 88% on 6-minute walk test 7
• Reduces symptoms and improves quality of life 7

Exercise Training: 7

• Structured exercise therapy reduces symptoms and improves 6-minute walk distance 7

Lung Transplant Evaluation: 7

• Refer for transplant evaluation in patients with advanced ILD 7
• Median survival post-transplant is 5.2-6.7 years versus <2 years without transplant in advanced disease 7

Critical Pitfalls to Avoid

• Do not diagnose IPF without excluding CTD, HP, and drug-induced ILD 1, 4
• Do not use corticosteroids for confirmed UIP/IPF (no benefit, significant harm) 1, 5
• Do not delay HRCT if functional decline occurs—do not wait for scheduled 12-month interval 2
• Do not perform transbronchial biopsy when surgical lung biopsy is feasible (inadequate sampling) 1
• Do not overlook prone positioning on HRCT to distinguish true subpleural opacity from dependent atelectasis 1
• Inadequate HRCT image quality necessitates repeat study 2
• Delayed recognition of progressive fibrosis may miss treatment escalation window 2