Idiopathic pulmonary fibrosis
Description
- Chronic, progressive fibrosing interstitial pneumonia of unknown cause, limited to the lungs
- Histological and radiological pattern = UIP
- Diagnosis of exclusion - requires no identifiable cause after full CTD, exposure and drug assessment
The UIP pattern
- Spatial heterogeneity - normal lung adjacent to fibrosis
- Temporal heterogeneity - fibroblastic foci (young) next to dense collagen (old)
- Subpleural, basal, peripheral predominance; honeycombing
- UIP pattern is NOT specific to IPF - also chronic hypersensitivity pneumonitis, CTD-ILD (esp. RA), asbestosis, drug toxicity, familial fibrosis
Progressive pulmonary fibrosis (PPF)
- A behaviour, not a diagnosis: any non-IPF fibrosing ILD meeting 2 of 3 within 12 months
- Worsening symptoms
- dec FVC >=5% absolute or dec DLCO >=10%
- Radiological progression
- Matters because PPF is treated like IPF - antifibrotics, not immunosuppression
Epidemiology
- Incidence ~3-9/100,000/yr; rising
- M>F (~2:1), age >60 (IPF under 50 should prompt a hunt for familial disease, CTD or telomeropathy)
- >=70% ever-smokers
- Median survival from diagnosis ~3-5 yr untreated - worse than many cancers
- Familial in ~5-20%
Aetiopathogenesis
The current model - epithelial, not inflammatory
- Repetitive alveolar epithelial (AT2 cell) micro-injury in a genetically susceptible, aged lung
- -> aberrant epithelial repair, senescence, ER stress
- -> TGF-beta, PDGF, FGF, CTGF release
- -> fibroblast -> myofibroblast transformation
- -> excess ECM deposition + architectural destruction -> honeycombing
- *Inflammation is not the driver* - this is why immunosuppression fails and harms
Genetics
- MUC5B promoter variant (rs35705950) - largest genetic effect in both sporadic and familial IPF
- Present in ~35% of IPF; low penetrance; paradoxically associated with better survival
- Mucus hypersecretion in the distal airway
- Telomere maintenance: TERT, TERC, RTEL1, PARN, OBFC1
- Short telomeres -> worse survival, poorer tolerance of immunosuppression
- Look for the extrapulmonary triad: premature greying, bone marrow failure, cryptogenic cirrhosis
- Surfactant genes: SFTPC, SFTPA2, ABCA3
- Epithelial barrier/host defence: DSP, DPP9, ATP11A, TOLLIP
- TOLLIP genotype modifies N-acetylcysteine response
Risk factors
- Smoking, age, male sex
- GORD and microaspiration (association, causality unproven)
- Occupational dust - metal, wood, stone, silica
- Chronic viral infection (EBV, herpesviruses)
Physiology
- Fibrosis -> dec lung compliance (stiff lung) -> restrictive defect
- Contrast COPD: inc compliance from loss of elastic recoil
- Loss of alveolar-capillary units -> dec DLCO
- V/Q mismatch + diffusion limitation -> exertional desaturation before resting hypoxaemia
Diagnosis
Requires: (1) exclusion of other causes, (2) UIP pattern on HRCT, or specific HRCT + histology combinations - decided at MDT.
Clinical
- Insidious exertional dyspnoea + dry cough over months-years
- Fine, dry, end-inspiratory "Velcro" crackles at the bases - often precede radiological change
- Clubbing (~50%)
- Late: pulmonary hypertension (loud P2, parasternal heave, inc JVP), cor pulmonale
- *Absent: wheeze, purulent sputum, systemic features. Their presence points elsewhere*
HRCT - the central test (inspiratory + expiratory + prone)
| Category | Features |
|---|---|
| UIP | Honeycombing +/- traction bronchiectasis; subpleural, basal, heterogeneous |
| Probable UIP | Reticulation + traction bronchiectasis, subpleural/basal, no honeycombing |
| Indeterminate | Subpleural basal fibrosis not meeting the above |
| Alternative diagnosis | See below |
- *In the right clinical context, a definite UIP pattern on HRCT is sufficient - no biopsy needed*
- Features that argue AGAINST IPF: upper/mid-zone predominance, peribronchovascular distribution, extensive ground glass, mosaic attenuation / air trapping (-> hypersensitivity pneumonitis), cysts, nodules, consolidation, pleural plaques (-> asbestosis), marked lymphadenopathy
Exclude a cause - the work that defines "idiopathic"
- Detailed exposure history: birds, feather bedding, mould, hot tubs, humidifiers, occupation, hobbies
- Drugs: amiodarone, methotrexate, nitrofurantoin, bleomycin, busulfan, checkpoint inhibitors, radiotherapy
- Serology in everyone: ANA, ENA, RF, anti-CCP, myositis panel (anti-Jo-1 and the antisynthetase set), anti-MDA5, ANCA, CK
- A significant minority of "IPF" is undeclared CTD-ILD or chronic HP - the commonest diagnostic error
Lung function
- Restrictive: dec FVC, dec TLC, dec RV, normal or inc FEV1/FVC ratio
- dec DLCO - often the earliest and most sensitive abnormality
- A combined pulmonary fibrosis and emphysema (CPFE) patient may have normal spirometry with a strikingly low DLCO and severe pulmonary hypertension
- 6MWT with oximetry - desaturation <88% predicts mortality
Bronchoscopy / biopsy
- BAL - only to exclude alternatives (lymphocytosis >30% suggests HP or NSIP; not diagnostic of IPF)
- Surgical lung biopsy or transbronchial cryobiopsy if HRCT is probable/indeterminate/alternative and the result would change management
- *MDT discussion (respiratory + radiology + pathology) is the diagnostic gold standard*
Fibrosis by zone - the exam discriminator
| Upper zone | Lower zone |
|---|---|
| CHARTS: Coal worker's, Hypersensitivity pneumonitis, Ankylosing spondylitis, Radiation, TB/Sarcoid, Silicosis, ABPA | RASIO: RA, Asbestosis, Scleroderma/CTD, IPF, Other drugs (amiodarone, nitrofurantoin, methotrexate, bleomycin) |
Peripheral signs pointing to a cause
- Clubbing -> IPF, asbestosis
- Deforming symmetrical polyarthropathy -> RA
- Sclerodactyly, microstomia, beaked nose, telangiectasia -> systemic sclerosis
- Mechanic's hands, Gottron papules, proximal weakness -> antisynthetase / myositis
- Lupus pernio -> sarcoidosis
- Slate-grey skin -> amiodarone
- Tattoo mark with demarcated erythema -> radiation
- Question-mark posture, dec chest expansion -> ankylosing spondylitis
Management
1. Antifibrotic therapy - offer to everyone with IPF
Neither reverses fibrosis. Both slow FVC decline by roughly half. Choose on side-effect profile and comorbidity.
| Nintedanib | Pirfenidone | |
|---|---|---|
| Mechanism | TKI - FGFR, PDGFR, VEGFR | Inhibits TGF-beta signalling, collagen synthesis, TNF |
| Effect | dec FVC decline ~50% | dec FVC decline ~50% |
| Key adverse effects | Diarrhoea (>60%), nausea, weight loss, transaminitis, bleeding, arterial thrombotic events, GI perforation | Nausea, anorexia, weight loss, photosensitivity rash, transaminitis |
| Cautions | Anticoagulation, recent MI, bowel surgery/diverticulitis | Sun protection mandatory |
| Interactions | P-gp / CYP3A4 | CYP1A2: inc by fluvoxamine, ciprofloxacin; dec by smoking and omeprazole |
- LFTs monthly for 6 months, then 3-monthly for both
- Neither has a clear mortality benefit in isolation; both reduce acute exacerbations
- Nintedanib also licensed for PPF and SSc-ILD
- Nerandomilast (preferential PDE4B inhibitor) - FDA-approved for IPF (2025) and PPF; reduced FVC decline at 52 weeks with or without background antifibrotic (FIBRONEER-IPF/ILD)
- Not yet in the 2022 ATS/ERS guideline; Australian availability lagging - check current PBS status
2. Do not use - actively harmful
- *Prednisolone + azathioprine + N-acetylcysteine (PANTHER-IPF: inc mortality and hospitalisation)*
- Warfarin (inc mortality), ambrisentan (inc progression), bosentan, macitentan, sildenafil, imatinib, everolimus, interferon-gamma
- *Immunosuppression has no place in IPF* - a patient on steroids for "IPF" almost certainly has a different diagnosis
- Exception: short-course corticosteroid in an acute exacerbation, on weak evidence
3. Non-pharmacological - equal priority
- Pulmonary rehabilitation - improves exercise capacity and QoL (benefit wanes without maintenance)
- Ambulatory and long-term oxygen for resting or exertional hypoxaemia
- Smoking cessation; influenza, pneumococcal, COVID-19, RSV vaccination
- Treat GORD if symptomatic (asymptomatic acid suppression is not recommended - inc pulmonary infection)
- Early palliative care - opioids for refractory dyspnoea and cough; cough is often the most distressing symptom and responds poorly to everything
4. Lung transplantation
- *Refer at diagnosis, not at deterioration* - IPF has the highest waitlist mortality of any transplant indication
- Consider if: DLCO <40%, FVC <80% or falling, any oxygen requirement, progression despite antifibrotic
- Age is a relative, not absolute, barrier
5. Acute exacerbation of IPF
- Acute (<1 month) worsening + new bilateral ground glass on HRCT, not fully explained by cardiac failure or fluid overload
- Mortality ~50% in hospital, median survival 3-4 months - the commonest cause of death
- Exclude infection, PE, pneumothorax, heart failure
- High-dose corticosteroid is usual but unproven; antibiotics empirically
- *Mechanical ventilation carries very poor outcomes - discuss ceilings of care in advance*
6. Monitor
- FVC and DLCO 3-6 monthly - a >=10% FVC decline over 6-12 months predicts mortality
- 6MWT with oximetry, symptoms, oxygen requirement
- Echo for pulmonary hypertension if disproportionate dyspnoea or desaturation
Associations
- Pulmonary hypertension (30-50% in advanced disease) - disproportionate dyspnoea and dec DLCO; poor prognosis
- Emphysema (CPFE) - preserved lung volumes, very low DLCO, severe PH, worse survival
- Lung cancer - ~5-10x risk, independent of smoking; often peripheral, in fibrotic zones; biopsy and resection can trigger an acute exacerbation
- Ischaemic heart disease and VTE - inc prevalence
- GORD - >80%, frequently silent
- OSA - up to 60%
- Depression, anxiety, deconditioning
- Telomeropathy syndromes - aplastic anaemia, MDS, cryptogenic cirrhosis, premature greying
- Familial pulmonary fibrosis - ask about affected relatives; genetic counselling
Natural history & complications
- Median survival ~3-5 yr from diagnosis untreated; antifibrotics slow but do not halt decline
- Course is unpredictable:
- Slow steady decline (most)
- Prolonged stability then rapid decline
- Acute exacerbations - abrupt, ~50% in-hospital mortality
- Death: respiratory failure ~40%; also acute exacerbation, IHD, PE, lung cancer, infection
Poor prognostic markers
- DLCO <40%, FVC <50%
- dec FVC >=10% or dec DLCO >=15% over 6-12 months - the strongest single predictor
- 6MWT desaturation <88% or distance <250 m
- Pulmonary hypertension, extent of honeycombing/fibroblastic foci
- GAP index (Gender, Age, Physiology - FVC and DLCO) - stages I-III, predicts 1/2/3-yr mortality
- Short telomeres
What to monitor for
- Acute exacerbation, pulmonary hypertension, lung cancer, VTE, hypoxaemia
- Discuss prognosis and advance care planning early - the trajectory is unpredictable and the terminal phase is often short
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