Key Facts

Interstitial lung disease (ILD) refers to a large group of conditions that affect the lung parenchyma (interstitium, alveoli, and small airways). They share features of restrictive physiology, impaired gas transfer, and characteristic imaging patterns but differ markedly in aetiology, natural history, and response to treatment.

Epidemiology

The overall incidence of ILD in the UK is approximately 30 per 100,000 per year. IPF is the commonest idiopathic ILD, with an incidence of 7-10 per 100,000 and a prevalence of 15-40 per 100,000. Mean age at diagnosis of IPF is 70 years with a male predominance (2:1). Connective tissue disease-associated ILD is common — up to 80% of systemic sclerosis patients develop ILD.

Aetiology

Known cause:

• Connective tissue disease: RA, systemic sclerosis (most common CTD-ILD), dermatomyositis, SLE, Sjögren syndrome
• Occupational/environmental: asbestosis, silicosis, coal workers' pneumoconiosis, hypersensitivity pneumonitis (bird fancier's lung, farmer's lung)
• Drug-induced: amiodarone, methotrexate, nitrofurantoin, bleomycin, cyclophosphamide
• Radiation pneumonitis

Idiopathic interstitial pneumonias (IIPs):

• IPF (most common, worst prognosis)
• NSIP (non-specific interstitial pneumonia — better prognosis)
• COP (cryptogenic organising pneumonia)
• DIP (desquamative interstitial pneumonia)
• RB-ILD (respiratory bronchiolitis-ILD)
• AIP (acute interstitial pneumonia — Hamman-Rich syndrome)

Pathophysiology

Repeated alveolar epithelial injury triggers aberrant wound healing with fibroblast/myofibroblast activation, excessive extracellular matrix deposition, and architectural distortion. In IPF, the TGF-β pathway is central. Fibrosis reduces lung compliance (restrictive defect) and thickens the alveolar-capillary membrane (impaired gas transfer). Honeycombing represents end-stage fibrosis with cystic destruction of the lung architecture.

Typical Presentation

• Progressive exertional dyspnoea (over months to years; weeks in AIP)
• Dry, non-productive cough
• Bibasal fine inspiratory crackles ("Velcro crackles" — characteristic of IPF/UIP)
• Finger clubbing (40% of IPF; uncommon in NSIP)
• Features of underlying CTD: Raynaud's, sclerodactyly, joint swelling, skin rash

Subacute/Acute Presentations

• Acute exacerbation of IPF: rapid deterioration over days-weeks, high mortality (~50%)
• AIP (Hamman-Rich): fulminant respiratory failure
• Drug-induced ILD: temporal relationship with drug exposure

Red Flags

• Rapidly progressive dyspnoea (AIP, acute exacerbation of IPF)
• SpO₂ <88% on exertion (significant gas transfer impairment)
• Weight loss (consider malignancy or CTD)
• Haemoptysis (consider malignancy, DAH, vasculitis)
• New systemic symptoms (rash, arthralgia) — CTD-ILD or vasculitis

Bedside

• SpO₂ at rest and on exertion (6-minute walk test with oximetry)
• Full history: occupational/environmental exposures, drug history, CTD symptoms, smoking, family history

Bloods

• Autoimmune screen: ANA, ENA (anti-Scl70, anti-Jo1, anti-RNP), RF, anti-CCP, myositis panel
• Serum precipitins: avian, fungal antigens (hypersensitivity pneumonitis)
• ACE level, serum calcium: sarcoidosis
• FBC, CRP, ESR: inflammatory markers
• LDH: often raised in ILD
• KL-6: biomarker for ILD activity (not widely available in UK)

Imaging

• CXR: bilateral reticular/reticulonodular opacities (often basal)
• HRCT thorax: gold standard — pattern recognition is key:
  • UIP: basal, subpleural honeycombing, traction bronchiectasis, minimal ground-glass
  • NSIP: basal ground-glass with subpleural sparing
  • COP: peripheral consolidation, migratory
  • HP: upper/mid zone ground-glass, mosaic attenuation, air trapping

Special Tests

• Pulmonary function tests: restrictive pattern (↓FVC, ↓TLC), ↓DLCO, preserved FEV₁/FVC
• Bronchoalveolar lavage (BAL): lymphocytosis (HP, sarcoidosis, NSIP), eosinophilia (eosinophilic pneumonia), neutrophilia (IPF/UIP)
• Surgical lung biopsy (VATS): when HRCT pattern indeterminate and diagnosis would change management
• Cryobiopsy: emerging alternative to surgical biopsy with lower morbidity

Non-pharmacological

• ILD MDT discussion: essential for accurate diagnosis and management plan
• Smoking cessation: critical (especially RB-ILD, DIP)
• Allergen/exposure avoidance: HP, occupational ILD
• Pulmonary rehabilitation: improves exercise tolerance and QoL in ILD
• Supplemental oxygen: for resting SpO₂ <88% or exertional desaturation
• Vaccination: influenza (annual), pneumococcal, COVID-19

Pharmacological

• IPF — antifibrotics (NICE NG228):
  • Pirfenidone 267 mg TDS increasing to 801 mg TDS over 2 weeks — slows FVC decline (CAPACITY and ASCEND trials)
  • Nintedanib 150 mg BD — slows FVC decline (INPULSIS trials); also licensed for progressive fibrosing ILD (INBUILD trial)
• Non-IPF inflammatory ILD: prednisolone 0.5-1 mg/kg/day (max 60 mg) tapering over months; steroid-sparing agents (azathioprine 2-3 mg/kg/day, mycophenolate 1-1.5 g BD)
• CTD-ILD: treat underlying CTD; mycophenolate first-line for SSc-ILD (SLS II trial); rituximab if refractory
• AVOID immunosuppression in IPF: prednisolone + azathioprine + NAC increases mortality (PANTHER-IPF trial)

Surgical/Interventional

• Lung transplantation: consider if FVC <50% predicted, DLCO <40%, declining despite treatment, age appropriate
• Surgical lung biopsy (VATS): for diagnostic uncertainty

Referral Criteria

• All suspected ILD to specialist ILD service for MDT discussion
• Transplant assessment if progressive disease despite treatment
• Palliative care referral for symptomatic progressive fibrotic ILD

IPF has the worst prognosis of the IIPs: median survival 3-5 years from diagnosis (antifibrotics slow but do not halt decline). NSIP has significantly better prognosis (5-year survival ~80%). COP typically responds well to steroids (>80% respond). Drug-induced ILD usually improves on withdrawal. Acute exacerbation of IPF carries ~50% in-hospital mortality. Progressive fibrosing ILD (non-IPF) has variable prognosis but progressive decline despite immunosuppression confers poor outcome.

HRCT Pattern Recognition

Key Trials in ILD