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Idiopathic Pulmonary Fibrosis (IPF)

Overview

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Epidemiology

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Etiology & Risk Factors

• Cigarette smoking — strongest modifiable risk factor
• Occupational exposures: metal dust (steel, brass), wood dust, stone dust, farming
• Gastroesophageal reflux disease (GERD) — microaspiration implicated
• Genetic factors:
  • Telomere-related gene mutations (TERT, TERC, RTEL1, PARN) in ~25% of familial and ~3% of sporadic IPF
  • MUC5B promoter variant (rs35705950) — found in ~38% of IPF patients vs. ~9% of controls; strongest known genetic risk factor
  • Surfactant protein mutations (SFTPC, SFTPA2)
• Viral infections: EBV, CMV, HHV-7, HHV-8 — proposed but unproven
• Family history: ~2–5% of IPF is familial (familial pulmonary fibrosis)

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Pathophysiology

1. Repetitive alveolar epithelial injury (from inhaled agents, GERD microaspiration, viral insults) → type II pneumocyte damage
2. Dysregulated repair: instead of normal re-epithelialization, there is activation of fibroblasts and myofibroblasts
3. Fibroblastic foci formation — key histologic hallmark: clusters of myofibroblasts depositing collagen beneath denuded epithelium
4. TGF-β signaling is central — drives myofibroblast differentiation, extracellular matrix (ECM) deposition, and inhibits matrix degradation
5. Shortened telomeres (in genetic forms) → accelerated alveolar epithelial senescence → impaired regeneration
6. Progressive architectural distortion → honeycombing → respiratory failure

Importantly, inflammation is NOT the primary driver (unlike many other ILDs), which is why steroids and immunosuppressants are ineffective and potentially harmful.

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Clinical Features

Symptoms

• Progressive exertional dyspnea — cardinal symptom, insidious onset
• Dry, nonproductive cough — often refractory
• Fatigue, weight loss (later stages)
• No fever, no hemoptysis (absence helps distinguish from other ILDs)

Signs

• Velcro-like inspiratory crackles — bibasilar, fine, dry (present in ~90%)
• Digital clubbing — ~50% of patients
• Signs of cor pulmonale (elevated JVP, pedal edema) in advanced disease
• Cyanosis in end-stage disease

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Diagnosis

Diagnostic Algorithm

Suspected IPF (age >60, male, smoker, bibasilar crackles, restrictive PFTs)
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Exclude known causes of ILD (CTD, drug toxicity, hypersensitivity pneumonitis, occupational)
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HRCT Thorax
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UIP pattern → IPF diagnosis (no biopsy needed in appropriate clinical context)
Probable UIP / Indeterminate → Consider surgical lung biopsy or TBLC
Non-UIP → Consider alternative diagnosis

HRCT — UIP Pattern Categories (ATS/ERS 2022)

Histopathology — UIP Pattern

• Fibroblastic foci (key feature)
• Heterogeneous fibrosis — temporal and spatial heterogeneity (old scar + active fibrosis side by side)
• Honeycombing with bronchiolar metaplasia
• Subpleural, paraseptal distribution
• Absence of features suggesting alternative diagnosis (granulomas, organizing pneumonia, prominent inflammation)

Pulmonary Function Tests (PFTs)

Laboratory / Other

• ANA, RF, anti-CCP, myositis panel, anti-Scl-70 — to exclude connective tissue disease-ILD (CTD-ILD)
• Genomic classifier (Envisia): gene expression testing on BAL; can help distinguish UIP from non-UIP without surgical biopsy
• BAL: not diagnostic for IPF; helps exclude infection, HP, or malignancy
• Serum KL-6 and SP-D: elevated; biomarkers of disease activity (used more in Japan)

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Differential Diagnosis

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Management

General Principles

• No curative treatment exists; goal is to slow progression, manage symptoms, prevent complications
• All patients should be evaluated for lung transplantation early
• Smoking cessation is mandatory
• Treat GERD aggressively (proton pump inhibitors)

Pharmacologic Treatment

Antifibrotic Therapy (First-line)

• Reduce rate of decline in FVC (not reversal)
• Do NOT improve symptoms or quality of life significantly
• Can be used in combination (evidence emerging)
• Should be continued lifelong unless intolerable

Treatments to AVOID

• Corticosteroids + azathioprine + N-acetylcysteine (NAC) triple therapy — shown to increase mortality (PANTHER-IPF trial, 2012)
• Corticosteroid monotherapy — not effective
• Anticoagulation (warfarin) — increased mortality (ACE-IPF trial)

Non-Pharmacologic Management

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Acute Exacerbation of IPF (AE-IPF)

• Incidence: ~5–10%/year
• Triggers: surgery, BAL, infection, aspiration (or idiopathic)
• HRCT: new bilateral GGO ± consolidation superimposed on UIP background
• Histology: diffuse alveolar damage (DAD) on UIP background
• Mortality: >50% in-hospital; survivors rarely return to baseline
• Treatment: empiric high-dose corticosteroids (IV methylprednisolone), supportive care; no proven therapy

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Complications

• Pulmonary hypertension (PH-ILD) — in up to 40%; independently worsens prognosis
• Lung cancer — 3–5× increased risk; squamous and adenocarcinoma most common
• Venous thromboembolism — increased risk
• Respiratory failure — end-stage
• Depression and anxiety — common; impacts QoL significantly
• Acute exacerbations — see above

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Prognosis

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Summary Table

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