Interstitial Lung Diseases (ILD)

Interstitial lung disease (ILD) is an umbrella term for a heterogeneous group of over 200 parenchymal lung disorders characterised by varying degrees of inflammation and fibrosis of the pulmonary interstitium. These conditions share common presenting features — progressive exertional dyspnoea, non-productive cough, and diffuse bilateral infiltrates on imaging — but differ vastly in aetiology, prognosis, and management.

In Australia, ILD prevalence is estimated at 60–80 per 100,000 population, with idiopathic pulmonary fibrosis (IPF) accounting for approximately 25–35% of all ILD diagnoses. IPF incidence rises sharply with age, with a median age at diagnosis of 65–70 years and a male-to-female ratio of approximately 1.5:1. Median survival from diagnosis remains 3–5 years — worse than many cancers.

The Australian IPF Registry (AIPFR), coordinated through the Lung Foundation Australia, has provided critical data on Australian disease patterns, comorbidities, and treatment outcomes. Key Australian data show that the median time from symptom onset to diagnosis is 12–18 months, highlighting the need for greater awareness among primary care clinicians.

Hypersensitivity pneumonitis is an important ILD subtype in Australia due to occupational and environmental exposures including bird keeping (budgerigar fancier's lung), farming, and mould exposure in tropical climates. Sarcoidosis shows lower prevalence in Australian Indigenous populations compared with African-American populations in the United States, but remains under-recognised in Aboriginal and Torres Strait Islander communities.

Major ILD Subtypes

ILDs are broadly classified into those with known causes and idiopathic forms. The 2013 ATS/ERS classification, updated in 2018 and 2022, provides the framework used in Australian practice:

HRCT Patterns and Diagnostic Significance

High-resolution computed tomography (HRCT) is the cornerstone of ILD diagnosis. A thin-section (1–1.5 mm) volumetric HRCT performed at full inspiration with expiratory images is the minimum standard in Australian centres. HRCT patterns are classified according to the 2018 ATS/ERS/JRS/ALAT guidelines:

Multidisciplinary Discussion (MDD)

Australian and international guidelines mandate that ILD diagnosis be made through multidisciplinary discussion involving a respiratory physician, thoracic radiologist, and lung pathologist, with rheumatology input when CTD-ILD is suspected. The MDD improves diagnostic accuracy from ~70% (individual clinician) to >90% and is recommended as best practice by the Thoracic Society of Australia and New Zealand (TSANZ).

Dedicated ILD MDD meetings are available at major Australian tertiary centres including Royal Melbourne Hospital, Alfred Health, Royal Brisbane and Women's Hospital, Royal Prince Alfred Hospital, and Fiona Stanley Hospital. Telemedicine MDD platforms are increasingly used to improve access for regional and remote Australian patients.

Lung Biopsy Indications

UIP Pattern on HRCT

The definitive HRCT diagnosis of IPF requires a UIP pattern (ATS/ERS 2018 update). The key features are:

• Typical UIP: Subpleural and basal predominant honeycombing with or without traction bronchiectasis, and minimal ground-glass opacity. No features inconsistent with UIP (upper/mid-zone or peribronchovascular predominance, extensive ground-glass, profuse micronodules, discrete cysts, mosaic attenuation with air trapping on three lobes, consolidation).
• Probable UIP: Subpleural basal reticular abnormality with traction bronchiectasis (or bronchiectasis) but no honeycombing and no inconsistent features. Lung biopsy may be needed for confirmation.
• Indeterminate: Some features of UIP but atypical findings present — surgical lung biopsy usually required.
• Alternative diagnosis: Features suggesting CTD-ILD, HP, drug effect, or another specific diagnosis.

Antifibrotic Therapy

Two antifibrotic agents are approved and PBS-listed in Australia for IPF. Neither reverses established fibrosis, but both significantly slow the rate of FVC decline — the primary endpoint in clinical trials.

Disease Progression and Monitoring

IPF follows a variable course. Disease progression is defined by:

• Forced vital capacity (FVC) decline ≥10% relative over 12 months — major prognostic indicator
• FVC decline 5–10% relative — marginal progression; warrants close monitoring
• DLCO decline ≥15% relative — associated with mortality increase
• Progression on HRCT — increasing extent of fibrosis, honeycombing
• Acute exacerbation — rapid worsening over <1 month with new bilateral ground-glass opacities; mortality 50–80%

Monitoring schedule: PFTs (spirometry + DLCO) every 3–6 months; 6-minute walk test (6MWT) every 6 months; HRCT annually or if clinical worsening; GAP index at diagnosis and annually.

Interpretation: Stage I (0–3 points): median survival >5 years. Stage II (4–5 points): median survival 3–4 years. Stage III (6–8 points): median survival 1.5–2 years.

Lung Transplant Timing

IPF is the leading indication for lung transplantation in Australia. Referral should be made early — at the time of diagnosis or when any of the following are present:

• DLCO <40% predicted
• FVC decline ≥10% over 6 months
• Desaturation <88% on 6MWT
• Honeycombing on HRCT (UIP pattern)
• Hospitalisation for respiratory decline or acute exacerbation
• GAP score Stage II or III

Australian transplant centres: Alfred Health (Melbourne), St Vincent's Hospital (Sydney), Prince Charles Hospital (Brisbane), Royal Adelaide Hospital, Fiona Stanley Hospital (Perth). Median wait time in Australia is 6–18 months; living-donor lobar transplantation is occasionally performed. Contraindications include active malignancy, active infection, uncontrolled psychiatric illness, BMI >35, and non-adherence.

Antigen Identification

Hypersensitivity pneumonitis (HP) is an immunologically mediated inflammatory and/or fibrotic lung disease caused by inhalation of a causative antigen in a sensitised individual. In Australia, the most common exposures include:

A thorough occupational and environmental history is essential. Precipitating antibodies (IgG panels to avian antigens, moulds) support but do not confirm the diagnosis — positive serology is found in up to 50% of exposed but asymptomatic individuals. Bronchoalveolar lavage (BAL) showing lymphocytosis with a CD4:CD8 ratio <1 (or <2 with very high lymphocyte count) is characteristic but not pathognomonic.

Acute vs Chronic Hypersensitivity Pneumonitis

Steroid Therapy

Corticosteroids are the mainstay of treatment for subacute and chronic HP when antigen avoidance alone is insufficient:

Antigen Avoidance Strategies

Complete antigen avoidance is the most effective intervention and the only intervention that can halt disease progression. Strategies include:

• Remove birds from the home; bird cages, feathers, and droppings from living areas. Rehoming birds may be necessary.
• For occupational exposures: use P2/N95 respirators, improve ventilation, modify work practices, consider role change if severe disease.
• For mould-related HP: address water damage, improve ventilation, decontaminate HVAC systems; environmental assessment by occupational hygienist.
• Hot tub: drain, thoroughly clean, and ensure appropriate chlorination/bromination; consider discontinuation.
• Workers' compensation and WorkSafe claims should be initiated for occupationally acquired HP (varies by state/territory).

Staging (Chest Radiograph — Scadding Stage)

Extrapulmonary Manifestations

Sarcoidosis is a systemic disease affecting virtually any organ. Australian data suggest extrapulmonary involvement in 30–50% of patients. Key manifestations include:

Treatment Indications

Not all sarcoidosis requires treatment. Treatment is indicated when there is:

• Significant or progressive pulmonary involvement (declining FVC, worsening HRCT)
• Cardiac sarcoidosis (any evidence — treat regardless of symptoms)
• Neurosarcoidosis (any evidence — treat urgently)
• Severe ocular disease unresponsive to topical therapy
• Disfiguring skin disease (lupus pernio)
• Hypercalcaemia causing renal impairment
• Symptomatic systemic disease affecting quality of life

Immunosuppression

Cardiac Sarcoidosis

Neurosarcoidosis

Neurosarcoidosis requires urgent specialist management. Presentation includes cranial nerve palsies (especially facial nerve CN VII), aseptic meningitis, peripheral neuropathy, hypothalamic/pituitary dysfunction (diabetes insipidus), and spinal cord involvement. Diagnosis is supported by MRI brain with gadolinium (leptomeningeal enhancement), CSF analysis (elevated protein, lymphocytic pleocytosis, elevated ACE), and biopsy when accessible. Treatment: high-dose oral prednisolone (1 mg/kg/day) or IV methylprednisolone (1 g daily for 3–5 days), followed by steroid-sparing agents (methotrexate, mycophenolate, or infliximab for refractory cases).

ILD is a significant cause of morbidity and mortality in connective tissue diseases (CTDs). Screening for ILD is recommended at CTD diagnosis and periodically thereafter, particularly in high-risk populations. The three most important CTD-ILD associations in Australian practice are rheumatoid arthritis, systemic sclerosis, and inflammatory myositis.

Rheumatoid Arthritis-Associated ILD (RA-ILD)

• Prevalence: 5–10% of RA patients (HRCT-detected subclinical ILD may be as high as 20–30%)
• Risk factors: male sex, smoking history, high-titre RF/anti-CCP, older age at RA diagnosis, usual interstitial pneumonia (UIP) pattern
• Most common pattern: UIP (60–70%), followed by NSIP
• RA-ILD with UIP pattern has a prognosis similar to IPF (median survival 3–5 years)
• Methotrexate pneumonitis is a diagnosis of exclusion — do not assume methotrexate is the cause without MDD review; true methotrexate ILD is rare (<1%)
• Screen with HRCT at RA diagnosis if risk factors present; PFTs (spirometry + DLCO) annually

Systemic Sclerosis-Associated ILD (SSc-ILD)

SSc-ILD is the leading cause of death in systemic sclerosis. ILD prevalence is 40–80% on HRCT (depending on disease subtype — diffuse cutaneous SSc has higher risk than limited cutaneous SSc). Key Australian management principles:

• Baseline HRCT and PFTs at SSc diagnosis — all patients, regardless of respiratory symptoms
• Indicators of progressive ILD: Extent of ILD on HRCT >20%, FVC <70% predicted, FVC decline ≥10% over 12 months, diffuse cutaneous subtype, anti-Scl-70 (anti-topoisomerase I) antibody positivity
• First-line immunosuppression: Mycophenolate mofetil 1000–1500 mg PO BD (SLS I trial, Australian consensus)
• Nintedanib is PBS-listed (Authority Required) for SSc-ILD based on the SENSCIS trial, which demonstrated a 44% reduction in the annual rate of FVC decline
• Combination therapy (mycophenolate + nintedanib) may be considered for progressive SSc-ILD per SENSCIS post-hoc and INBUILD subgroup analyses

Myositis-Associated ILD

Inflammatory myositis (dermatomyositis, polymyositis, antisynthetase syndrome, immune-mediated necrotising myopathy) is complicated by ILD in 20–40% of cases. Myositis-associated ILD can be severe and rapidly progressive, particularly in the antisynthetase syndrome (anti-Jo-1, anti-PL-7, anti-PL-12, anti-EJ, anti-OJ antibodies) and anti-MDA5 antibody-positive clinically amyopathic dermatomyositis (which carries a risk of rapidly progressive ILD with high mortality).

Treatment of myositis-ILD follows a step-up approach:

• First-line: High-dose corticosteroids (prednisolone 1 mg/kg/day, wean over 6–12 months) + steroid-sparing agent (mycophenolate mofetil or azathioprine)
• Second-line / steroid-sparing: Rituximab (MabThera®) 1000 mg IV × 2 doses (day 1 and 15); evidence from RIM and MyoNet registries, increasingly used as early steroid-sparing strategy
• Refractory disease: IV immunoglobulin (IVIg) 2 g/kg over 2–5 days monthly; cyclophosphamide; calcineurin inhibitors (tacrolimus, cyclosporine); JAK inhibitors (tofacitinib) — emerging evidence
• Nintedanib may be added for progressive fibrotic CTD-ILD (INBUILD trial — included CTD-ILD subgroup)

Immunosuppressive Strategies — Summary

The pathophysiology of ILD varies by subtype but centres on three core mechanisms:

• Inflammation-driven: Inflammatory cells (lymphocytes, macrophages, neutrophils) infiltrate the alveolar walls and interstitium, causing alveolitis. This is the predominant mechanism in HP, sarcoidosis, and CTD-ILD. Immunosuppression can halt or reverse this process.
• Fibrosis-driven: Abnormal wound healing leads to myofibroblast proliferation, extracellular matrix deposition, and progressive scarring. Alveolar epithelial injury with aberrant repair is the central paradigm in IPF. TGF-β, PDGF, and FGF pathways are key mediators targeted by antifibrotic agents.
• Granulomatous: Non-caseating granulomas composed of epithelioid histiocytes, giant cells, and CD4+ T lymphocytes. The hallmark of sarcoidosis. Driven by exaggerated Th1 immune response.

In IPF, the current paradigm favours repeated micro-injury to the alveolar epithelium (genetic predisposition + environmental triggers such as smoking, dust, gastro-oesophageal reflux) leading to aberrant fibroblast activation and progressive fibrosis without significant preceding inflammation. This explains why immunosuppression is ineffective and potentially harmful in IPF.

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