RespiratoryTier 2Disease (DEADMAN)

Interstitial lung disease

Description

>200 disorders of the alveolar interstitium, sharing restrictive physiology + dec DLCO + diffuse parenchymal infiltrates
The diagnosis is a triad: clinical + HRCT + (sometimes) histology, settled at MDT

Classification - the framework to answer any ILD question

Group	Members
Known cause	CTD-ILD, drug-induced, hypersensitivity pneumonitis, pneumoconiosis (asbestos, silica, coal, beryllium), radiation
Idiopathic interstitial pneumonias	IPF (UIP), NSIP, COP, AIP, RB-ILD, DIP, LIP, PPFE
Granulomatous	Sarcoidosis, hypersensitivity pneumonitis, berylliosis, GPA
Other/distinct	LAM, pulmonary Langerhans cell histiocytosis, eosinophilic pneumonia, alveolar proteinosis, amyloid

Histological/radiological patterns - the vocabulary

Pattern	HRCT	Typical cause
UIP	Honeycombing, traction bronchiectasis, subpleural/basal, heterogeneous	IPF, RA-ILD, asbestosis, chronic HP, drug
NSIP	Ground glass +/- traction bronchiectasis, minimal honeycombing, temporally UNIFORM, subpleural sparing	Most CTD-ILD (SSc, myositis, Sjogren), drug, idiopathic
OP	Peripheral/peribronchial consolidation, migratory, reversed halo (atoll sign)	Cryptogenic OP, drug, infection, CTD, radiation
DAD	Diffuse ground glass + consolidation	AIP, ARDS, acute exacerbation of IPF
HP	Mosaic attenuation, air trapping on expiration, centrilobular nodules, upper/mid zone, "three-density sign"	Antigen exposure
LIP	Cysts + ground glass	Sjogren, HIV, common variable immunodeficiency
RB-ILD / DIP	Centrilobular nodules / ground glass, upper zone	Smoking

*UIP in a woman with a deforming polyarthropathy is RA-ILD, not IPF. RA is the one CTD where UIP dominates over NSIP.*

Progressive pulmonary fibrosis (PPF)

Any fibrosing non-IPF ILD meeting 2 of 3 in 12 months: worsening symptoms; dec FVC >=5% or dec DLCO >=10%; radiological progression
Changes the treatment axis from immunosuppression toward antifibrotic

Epidemiology

ILD prevalence ~70-80/100,000; sarcoidosis and IPF dominate in different age groups
IPF: M>F, >60, smokers
Sarcoidosis: 20-40 yr, F slightly >M; higher severity in African ancestry
CTD-ILD: F>M (follows the CTD); ILD is the leading cause of death in systemic sclerosis
HP: any age; bird and mould exposure; ~half have no identifiable antigen
Australia: accelerated silicosis in engineered-stone benchtop workers - a re-emerging occupational epidemic; engineered stone banned from 2024

Aetiopathogenesis

Two broad routes to fibrosis

Inflammation-driven (NSIP, OP, HP, CTD-ILD, sarcoid) -> responds to immunosuppression
Epithelial injury/aberrant repair driven (UIP/IPF) -> antifibrotic; immunosuppression is harmful
*Deciding which pathway dominates is the whole of ILD management*

Common mechanisms

Alveolar epithelial injury -> loss of AT1/AT2 integrity
-> fibroblast recruitment + myofibroblast transformation (TGF-beta, PDGF, CTGF)
-> collagen deposition, architectural distortion, loss of alveolar-capillary units
Genetic susceptibility: MUC5B, telomere genes (TERT, TERC, RTEL1), surfactant genes

Drug causes - ask about every one

Amiodarone (slate-grey skin, high uptake, very long half-life), methotrexate, nitrofurantoin, bleomycin (dose- and O2-related), busulfan, checkpoint inhibitors (pneumonitis), CAR-T, hydralazine, sulfasalazine, daptomycin (eosinophilic)
Reference www.pneumotox.com

Physiology

Stiff, non-compliant lung -> restrictive defect
Loss of alveolar-capillary surface + V/Q mismatch -> dec DLCO, exertional desaturation before resting hypoxaemia
Rapid shallow breathing pattern to minimise elastic work
Late: hypoxic vasoconstriction + vascular obliteration -> pulmonary hypertension -> cor pulmonale

Diagnosis

Clinical

Progressive exertional dyspnoea + dry cough; duration and tempo matter
- Days-weeks -> AIP, acute HP, drug, eosinophilic pneumonia, DAH, infection
- Months-years -> IPF, CTD-ILD, chronic HP, sarcoid, pneumoconiosis
Fine, late/pan-inspiratory "Velcro" crackles, best heard laterally in the axillae (the lower lobes wrap posterolaterally)
Clubbing - IPF, asbestosis; uncommon in sarcoid and HP
Reduced expansion, tachypnoea, cyanosis, cachexia
Signs of PH/cor pulmonale in advanced disease: loud P2, parasternal heave, inc JVP, oedema

Extrapulmonary signs - the diagnosis is usually outside the chest

Deforming symmetrical polyarthropathy, nodules -> RA
Sclerodactyly, telangiectasia, calcinosis, Raynaud, microstomia -> systemic sclerosis
Heliotrope rash, Gottron papules, mechanic's hands, proximal weakness -> dermatomyositis / antisynthetase
Sicca, parotid swelling -> Sjogren
Erythema nodosum, lupus pernio, uveitis, parotid/lacrimal swelling -> sarcoid
Pleural plaques, occupational history -> asbestos
Question-mark spine, dec chest expansion -> ankylosing spondylitis
Slate-grey skin -> amiodarone; tattoo/skin demarcation -> radiation

The exposure history is the investigation

Birds, feather duvets/pillows, mould, water damage, hot tubs, humidifiers, cheese, hay
Occupation: engineered stone benchtops (accelerated silicosis), mining, shipbuilding, insulation, welding, farming, beryllium
Hobbies, pets, home environment, smoking, drugs, radiotherapy
Take the history twice - HP antigens are commonly missed the first time

Lung function

Restrictive: dec FVC, dec TLC, dec RV; FEV1/FVC normal or raised
dec DLCO - the most sensitive marker; often abnormal before volumes
- A residual volume NOT proportionally reduced -> mixed obstructive-restrictive (sarcoid, HP, LAM, CPFE, smoking-related)
6MWT with continuous oximetry - desaturation <88% is prognostic
*In combined pulmonary fibrosis and emphysema, volumes may be normal with a strikingly low DLCO*

Imaging

CXR - reticulonodular shadowing; pleural plaques (asbestos), bihilar lymphadenopathy (sarcoid), eggshell calcification (silicosis)
HRCT - volumetric, inspiratory AND expiratory AND prone
- Prone distinguishes true early basal fibrosis from dependent atelectasis (which clears)
- Expiratory demonstrates air trapping - the key to hypersensitivity pneumonitis
- Assess: distribution (zone, axial), honeycombing, traction bronchiectasis, ground glass, nodules, cysts, mosaicism, nodes, oesophageal dilatation (-> systemic sclerosis)

Serology - in every new ILD

ANA + ENA, RF, anti-CCP, myositis panel (Jo-1 and the antisynthetase set, anti-MDA5, anti-Mi-2), anti-Scl-70, anti-centromere, anti-RNA polymerase III
ANCA (MPO -> vasculitis and MPO-ILD), anti-GBM if pulmonary-renal syndrome
CK, aldolase, ESR/CRP, ACE (neither sensitive nor specific for sarcoid)
FBC - eosinophilia (eosinophilic pneumonia, EGPA, drug), lymphopenia, cytopenias
Urinalysis; serum precipitins/specific IgG for suspected HP antigens (exposure marker, not disease)
Consider IPAF (interstitial pneumonia with autoimmune features) if serology or morphology is suggestive without a defined CTD

Bronchoscopy and biopsy

BAL - mainly to exclude infection, DAH, malignancy
- Lymphocytosis >30-50% -> HP, sarcoid, NSIP, drug, LIP
- Eosinophils >25% -> eosinophilic pneumonia; neutrophils -> UIP, infection, ARDS
- Progressively bloodier aliquots -> diffuse alveolar haemorrhage
- Milky, PAS-positive -> alveolar proteinosis
Transbronchial biopsy - high yield in sarcoid, OP, lymphangitis carcinomatosa; poor for UIP
- EBUS-TBNA for hilar/mediastinal nodes (sarcoid, lymphoma, malignancy)
Transbronchial cryobiopsy or surgical lung biopsy - when HRCT is not definitive and the answer changes treatment
Genomic classifier on transbronchial samples can identify a UIP molecular signature

Other

Echocardiography - screen for pulmonary hypertension and right heart strain
Hypoxaemia that improves on lying down (platypnoea) suggests a right-to-left shunt or hepatopulmonary syndrome, not ILD

Management

1. Remove the cause - the highest-yield intervention

Antigen avoidance in HP (rehome the birds, remediate mould) - may be curative in acute/subacute disease
Stop the drug; remove from occupational exposure and notify (silicosis, asbestosis are compensable)
Smoking cessation - curative in RB-ILD, DIP, PLCH

2. Decide the treatment axis - inflammatory vs fibrotic

	Inflammatory-predominant	Fibrotic-predominant
Clues	Ground glass, NSIP/OP pattern, CTD, HP, sarcoid, short history	Honeycombing, UIP pattern, traction bronchiectasis, slow progression
Treat with	Immunosuppression	Antifibrotic

*In IPF, immunosuppression increases mortality (PANTHER-IPF). Never give prednisolone/azathioprine/NAC for IPF.*

3. Immunosuppression - inflammatory ILD

Corticosteroid for induction (sarcoid, OP, acute HP, eosinophilic pneumonia, CTD-ILD flare)
- OP responds dramatically but relapses in ~50% on withdrawal - taper slowly over 6-12 months
Mycophenolate is the preferred first-line steroid-sparing agent across CTD-ILD (ACR/CHEST 2023)
- Alternatives: azathioprine, rituximab; cyclophosphamide for severe or rapidly progressive disease
- *Long-term glucocorticoids are recommended AGAINST in RA-ILD and systemic sclerosis*
- Corticosteroid in systemic sclerosis (esp. >15 mg/day) risks scleroderma renal crisis**
Systemic sclerosis-ILD: mycophenolate (SLS-II), tocilizumab (early inflammatory, raised CRP), nintedanib (SENSCIS), rituximab; autologous HSCT in selected severe diffuse disease
Anti-MDA5 dermatomyositis with rapidly progressive ILD - very high mortality; triple therapy (steroid + calcineurin inhibitor + cyclophosphamide/rituximab) early
Myositis-ILD: steroid + mycophenolate/azathioprine/tacrolimus; IVIg

4. Antifibrotics

Nintedanib - IPF, SSc-ILD, and progressive pulmonary fibrosis of any cause
Pirfenidone - IPF; evidence in unclassifiable progressive fibrosis
Nerandomilast (PDE4B inhibitor) - approved in IPF and PPF (FIBRONEER programme); check Australian availability
Antifibrotic and immunosuppression are not mutually exclusive in PPF - the choice depends on pace, fibrotic burden and UIP pattern

5. Sarcoidosis-specific

Most stage I disease resolves spontaneously - observe
Treat if: symptomatic/progressive lung disease, cardiac, neurological, ocular, renal, hypercalcaemia
Prednisolone -> methotrexate/azathioprine/mycophenolate -> infliximab for refractory

6. Supportive - for every ILD, at every stage

Pulmonary rehabilitation
Ambulatory and long-term oxygen for resting or exertional hypoxaemia
Vaccination (influenza, pneumococcal, COVID-19, RSV)
Treat comorbidity: GORD, OSA, pulmonary hypertension, deconditioning, anxiety
- Inhaled treprostinil for PH associated with ILD (group 3) - the one pulmonary vasodilator with positive evidence in this setting (INCREASE)
Palliative care and opioids for refractory dyspnoea and cough - cough is often the dominant symptom
Lung transplant referral early in progressive fibrotic disease

7. Monitor

FVC, DLCO 3-6 monthly; 6MWT; HRCT if change
dec FVC >=10% or dec DLCO >=15% = progression -> escalate or change axis
Screen for lung cancer risk in fibrotic ILD

Associations

Connective tissue disease - RA (UIP predominates), systemic sclerosis (NSIP), myositis/antisynthetase (NSIP/OP), Sjogren (NSIP/LIP), SLE (rarely fibrotic; serositis and shrinking lung), MCTD
Vasculitis - GPA, EGPA, MPO-ANCA-associated ILD
Sarcoidosis - erythema nodosum, uveitis, lupus pernio, hypercalcaemia, cardiac and neurological disease
Occupational - asbestosis (+ pleural plaques, mesothelioma), accelerated silicosis (engineered stone), coal worker's, berylliosis (mimics sarcoid)
Smoking-related - RB-ILD, DIP, pulmonary Langerhans cell histiocytosis (upper zone cysts + nodules + pneumothorax), CPFE
LAM - young women, tuberous sclerosis, cysts, chylothorax, recurrent pneumothorax, angiomyolipoma
Pulmonary hypertension, cor pulmonale
Lung cancer - increased risk in fibrotic ILD and asbestosis
GORD - very common in systemic sclerosis and IPF
Immunodeficiency - CVID -> granulomatous-lymphocytic ILD; HIV -> LIP

Natural history & complications

Prognosis is dictated by pattern and cause, not by the label "ILD"

	Course
IPF (UIP)	Relentless; median survival 3-5 yr
RA-ILD with UIP	Behaves like IPF - poor
NSIP	Better; often responsive to immunosuppression
COP	Excellent response to steroid; relapse in ~50%
Acute HP	Reversible with antigen removal
Chronic fibrotic HP	Can be as bad as IPF
Sarcoid stage I	~60-90% spontaneous remission
AIP	Fulminant; mortality >50%
Asbestosis	Slow, progresses despite exposure ceasing
Accelerated silicosis	Rapid, progressive, no effective therapy

Prognostic markers across ILDs

Baseline and serial FVC and DLCO - serial change outperforms any single value
DLCO <40%, desaturation on 6MWT, extent of fibrosis/honeycombing on HRCT
Pulmonary hypertension
GAP index (Gender, Age, Physiology) - validated across several ILDs
Development of PPF criteria

Complications

Progressive respiratory failure - the usual cause of death
Acute exacerbation - abrupt new ground glass, ~50% in-hospital mortality; occurs in non-IPF fibrotic ILD too
Pulmonary hypertension and cor pulmonale
Lung cancer
Pneumothorax - PLCH, LAM
Opportunistic infection from immunosuppression - PJP prophylaxis if prednisolone >=20 mg for >4 weeks or on cyclophosphamide/rituximab
Steroid complications: osteoporosis, diabetes, myopathy

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