ILD: Chest X-Ray Findings

Key Point: CXR vs. HRCT

Parenchymal Patterns on CXR

Distribution - a Key Diagnostic Clue

Basilar (Lower Zone) Predominance

• IPF (UIP pattern) - peripheral basal reticulation is the hallmark
• Connective tissue disease-associated ILD (RA, scleroderma)
• Asbestosis

Upper Zone Predominance

• Sarcoidosis
• Silicosis and coal worker's pneumoconiosis
• Pulmonary Langerhans cell histiocytosis (PLCH)
• Carmustine-induced fibrosis

Peripheral (Subpleural) Predominance

• Organizing pneumonia (COP)
• Chronic eosinophilic pneumonia

Associated (Ancillary) Findings

Classic CXR Appearance of IPF (UIP Pattern)

UIP Pattern - PA CXR with Microcystic Changes

Acute vs. Chronic Pattern

• Acute interstitial pattern (developing over hours to days): Think pulmonary edema (Kerley lines, cardiomegaly, effusions), atypical pneumonia (PCP, CMV, Mycoplasma)
• Chronic progressive pattern: Think IPF, CTD-ILD, sarcoidosis, pneumoconiosis, lymphangitic carcinomatosis

Limitations of CXR in ILD

• Cannot distinguish reticular from linear/nodular patterns reliably
• Cannot detect early honeycombing, traction bronchiectasis, or ground-glass opacities well
• HRCT is the gold standard - it enables pattern characterization (UIP, NSIP, DIP, etc.) and can guide whether biopsy is needed

ILD: Mortality and Morbidity

1. Overall Burden

2. Mortality by ILD Subtype

3. IPF - The Highest-Mortality ILD

• Median survival: 3-4 years after diagnosis (Murray & Nadel)
• Long periods of stability punctuated by acute exacerbations - each exacerbation carries 50-80% in-hospital mortality
• New antifibrotic therapies (nintedanib, pirfenidone) delay progression but have not yet clearly improved overall survival in pooled data

Factors Associated with Increased Mortality in IPF:

• Male sex and older age
• Lower FVC (forced vital capacity)
• Lower DLCO (diffusing capacity)
• FVC decline >10% over 6-12 months - strongest predictor of death
• Initiation of long-term oxygen therapy
• Occurrence of an acute exacerbation
• Presence of pulmonary hypertension

Prognostic Scoring Tools:

• GAP Index (Gender, Age, Physiology - FVC + DLCO) - validated across multiple fibrotic ILDs
• Composite Physiologic Index (CPI)
• Du Bois Prognostic Index

Note: These indices perform better at population level than for individual prediction. Studies show they may not outperform DLCO alone.

4. Major Causes of Morbidity

Respiratory

Cardiovascular

Oncologic

• Lung cancer risk is significantly elevated in IPF (5-10x the general population), likely due to shared fibrotic/inflammatory milieu and smoking history

Systemic / Other

5. Causes of Death in ILD

1. Respiratory failure (most common - progressive or acute-on-chronic)
2. Acute exacerbation of underlying ILD
3. Pulmonary hypertension / right heart failure
4. Lung cancer (especially in IPF)
5. Cardiovascular disease (comorbid)
6. Infections / sepsis (increased susceptibility, especially in immunosuppressed CTD-ILD patients)

6. CTD-Associated ILD Mortality

• Rheumatoid arthritis ILD (RA-ILD): A 2024 meta-analysis (PMID 39534599) identified biomarkers predictive of RA-ILD severity; RA-ILD contributes significantly to excess mortality in RA patients
• SSc-ILD: Treated with tocilizumab; 2024 meta-analysis (PMID 37773003) confirmed benefit in lung function stabilization
• Anti-MDA5 dermatomyositis-ILD: Rapid progressive form with >50% mortality if untreated; tofacitinib shows promise per 2024 meta-analysis (PMID 39480695)

7. Acute Exacerbation - A Key Mortality Event

Summary Table

Antifibrotic Therapies in ILD: Nintedanib and Pirfenidone

Overview

1. Pirfenidone

Mechanism

• Inhibits TGF-β-stimulated collagen synthesis
• Reduces fibroblast proliferation
• Suppresses production of profibrotic cytokines (TGF-β1, TNF-α, PDGF)
• Has anti-inflammatory properties in animal models of fibrosis

Key Pivotal Trials

Dosing

• Start: 267 mg three times daily (orally)
• Escalate weekly to: 801 mg three times daily by week 3
• Take with food to reduce GI side effects

Side Effects

2. Nintedanib

Mechanism

• PDGFR (platelet-derived growth factor receptor) - α and β
• VEGFR (vascular endothelial growth factor receptor) 1, 2, 3
• FGFR (fibroblast growth factor receptor) 1, 2, 3

Key Pivotal Trials

Dosing

• 150 mg orally twice daily (with food)
• Dose reduction to 100 mg twice daily if not tolerated

Side Effects

3. Head-to-Head Comparison

4. Impact on Mortality and Acute Exacerbations

• All-cause mortality reduced: pooled RR 0.55 (95% CI 0.45-0.66) with antifibrotic therapy
• Acute exacerbation risk reduced: pooled RR 0.63 (95% CI 0.53-0.76)
• Effect on AE was more consistent for nintedanib than pirfenidone in subgroup analyses
• Effect on mortality was consistent regardless of antifibrotic subtype

5. Use in Non-IPF Progressive Fibrosing ILD (PF-ILD)

• Anti-fibrotics significantly reduced FVC decline in non-IPF PF-ILD (MD -66.8 mL; p<0.01)
• Pirfenidone showed benefit in 6-minute walk distance
• No significant mortality benefit in this population vs. placebo
• Adverse events (GI, neurological) were significantly more frequent in the antifibrotic group

• Systemic sclerosis-associated ILD (SSc-ILD) - SENSCIS trial
• Progressive fibrosing ILDs (PF-ILD) of any cause - INBUILD trial

6. What These Drugs Do NOT Do

• Do not reverse fibrosis - they slow, not stop, progression
• Do not improve FVC - they reduce the rate of decline
• Do not cure IPF - lung transplant remains the only potentially curative option
• Combination therapy (both drugs together) is being explored but not yet standard

7. Practical Monitoring

How Long Should Antifibrotic Therapy (Nintedanib / Pirfenidone) Be Taken?

The Short Answer

Why Lifelong?

"Both pirfenidone and nintedanib reduce the rate of FVC decline by approximately 50% over 1 year of treatment... Studies to date suggest the adverse effects are manageable for the majority of patients with a reasonable long-term tolerability profile."

When to Continue

• The patient tolerates the drug (or tolerates a dose-reduced version)
• Disease is progressing (this is the indication - IPF always progresses, so treatment should continue)
• The patient has not proceeded to lung transplant
• The patient is not at end of life / comfort-focused care

When to Consider Stopping or Switching

What Happens If Stopped?

Dose Interruptions vs. Permanent Stops

• Nintedanib: can be held perioperatively and restarted once wound healing is adequate (due to anti-VEGF bleeding risk)
• Pirfenidone: can be temporarily held for LFT abnormalities or rash and restarted at lower dose with uptitration

Summary