Chronic Diffuse Interstitial (Restrictive) Lung Diseases

Overview & Classification

🔑 MNEMONIC: "FGSE" for ILD Categories

Fibrosing, Granulomatous, Smoking-related, Eosinophilic

IDIOPATHIC PULMONARY FIBROSIS (IPF) / Usual Interstitial Pneumonia (UIP)

Definition

Epidemiology

• Prevalence: 50-200 per 100,000
• Predominantly affects males > females
• Typically diagnosed in the 5th-6th decade (virtually never before age 50)
• Associated with smoking, air pollution, metal fumes, wood dust, farming, hairdressing, stone polishing
• Poor prognosis: 50% survival at 3-5 years

Pathogenesis

Fig. 15.13 - Robbins & Kumar Pathologic Basis of Disease: Pathogenic mechanisms in IPF

Environmental Triggers

• Cigarette smoking (greatest risk factor - increases risk several-fold)
• Air pollution, microaspiration, metal fumes, wood dust
• Farming, hairdressing, stone polishing occupations

Genetic Factors

• TERT, TERC, PARN, RTEL1 mutations (telomere maintenance genes) - up to 15% of familial IPF
• Surfactant gene mutations - cause protein misfolding → unfolded protein response → type II pneumocyte sensitization
• MUC5B promoter SNP - greatly increases MUC5B mucin secretion (alters mucociliary clearance)
• Up to 25% of sporadic IPF: abnormal telomere shortening in peripheral blood lymphocytes

The Fibrotic Cascade

1. Persistent alveolar epithelial injury/activation
2. Injured type II pneumocytes release TGF-β and other profibrotic factors
3. Innate/adaptive immune cells amplify the signal
4. Fibroblast/myofibroblast activation and proliferation
5. Excessive collagen deposition → interstitial fibrosis

🔑 MNEMONIC for IPF Risk Factors: "SAGE-TOM"

Smoking, Aging, Genetics (telomerase/MUC5B), Environmental exposure (dust/fumes) - Telomere shortening, Occupational (farming/stone polishing), Microaspiration (GERD)

Gross Pathology

• Pleural surfaces are cobblestoned due to retraction of scars along interlobular septa
• Cut surface: firm, rubbery, white areas of fibrosis, predominantly at the periphery/bases
• Subpleural and basilar predominance is characteristic
• End-stage: Honeycomb lung - dilated, cystic spaces resembling a honeycomb

Microscopy (Histopathology) - UIP Pattern

Fig. 11.14 (Robbins Basic Pathology): UIP pattern - patchy fibrosis, more pronounced subpleurally. Note honeycomb spaces on the left with dense inflammatory infiltrates.

Fig. 11.15 (Robbins Basic Pathology): Fibroblastic focus - fibers running parallel to surface with bluish myxoid extracellular matrix. Honeycombing is visible to the left.

🔑 MNEMONIC for UIP Microscopy: "FISH-TH"

Fibroblastic foci, Inflammation (lymphocytes/plasma cells), Spatial heterogeneity, Honeycombing - Temporal heterogeneity, Hyperplastic type II pneumocytes lining cysts

Radiology (HRCT) - UIP Pattern

FIGURE 304-2 (Harrison's 22E): A = IPF/UIP (posterior basilar subpleural reticulation + honeycombing + traction bronchiectasis); B = NSIP; C = COP; D = Sarcoidosis

• Posterior, basilar, subpleural predominance
• Reticular markings (irregular fibrotic lines)
• Traction bronchiectasis (airway distortion from surrounding fibrosis)
• Honeycombing (cystic spaces in rows, subpleural)

Histopathology Comparison - ILDs

FIGURE 304-3 (Harrison's 22E): A = IPF/UIP (honeycomb + fibroblast foci + temporal heterogeneity); B = NSIP (uniform inflammation/fibrosis); C = COP (organizing pneumonia plugs in small airways); D = Sarcoidosis (noncaseating granulomas)

Clinical Features

• Gradual onset of non-productive cough + progressive exertional dyspnea
• "Velcro" or "dry" bibasilar crackles on auscultation (characteristic)
• Digital clubbing (in ~50%)
• Late: cyanosis, cor pulmonale, peripheral edema
• Pulmonary function tests: restrictive pattern with reduced DLCO

Treatment

• Antifibrotic therapy: Pirfenidone (TGF-β inhibitor) and Nintedanib (tyrosine kinase inhibitor) - both slow the rate of FVC decline, approved since 2014
• Immunosuppression (steroids/azathioprine/NAC) - shown to increase morbidity and mortality in IPF; NOT recommended
• Supplemental O₂ + pulmonary rehabilitation for exercise tolerance
• Lung transplantation - only definitive treatment; extends survival

OTHER KEY CHRONIC DIFFUSE INTERSTITIAL DISEASES

Nonspecific Interstitial Pneumonia (NSIP)

Cryptogenic Organizing Pneumonia (COP)

Smoking-Related ILD

Respiratory Bronchiolitis-ILD (RB-ILD)

• Active heavy smokers, age 40-50
• Histology: pigmented macrophages in respiratory bronchioles and alveolar ducts (peribronchiolar)
• HRCT: centrilobular nodules, ground-glass, bronchial wall thickening
• Treatment: Smoking cessation (first and most important step)

Desquamative Interstitial Pneumonia (DIP)

• More diffuse than RB-ILD
• Histology: diffuse alveolar filling with pigmented macrophages + pneumocyte hyperplasia + prominent interstitial thickening
• HRCT: diffuse/patchy bilateral symmetric ground-glass opacities
• Treatment: smoking cessation ± steroids

Sarcoidosis (Granulomatous ILD)

Pulmonary Langerhans Cell Histiocytosis (PLCH)

• Young male smokers (2nd-3rd decade)
• Histology: interstitial Langerhans cells with Birbeck granules (X bodies on EM); CD1a+, S-100+ on IHC; peribronchiolar stellate fibrosis + cysts
• HRCT: upper/mid lung cysts + nodules; spares lung bases
• Somatic BRAF V600E mutations in many cases
• Treatment: smoking cessation; corticosteroids; vemurafenib (BRAF V600E+)
• Spontaneous pneumothorax in ~25%

Summary Comparison Table

🔑 Master Mnemonic - ILD Quick Review: "IPF needs PIRFENIDONE - Fibrosis Is Scary History"