Interstitial Lung Disease (ILD) — Causes, Diagnosis & Treatment Guide — Symptoms, Causes & Treatment | MyMedicPlus

Interstitial lung disease (ILD), also termed diffuse parenchymal lung disease (DPLD), is a broad category of over 200 conditions characterised by inflammation and fibrosis of the lung interstitium — the connective tissue scaffolding between alveoli — leading to diffuse alveolar damage, impaired gas exchange, and progressive restrictive respiratory failure. The term 'interstitial' is somewhat misleading as the pathological process frequently also involves alveolar walls, airspaces, and small airways. ILD causes progressive dyspnoea, a restrictive ventilatory defect on spirometry (reduced FVC and TLC with preserved FEV1/FVC ratio), reduced diffusing capacity for carbon monoxide (DLCO), and bilateral infiltrates on chest X-ray and high-resolution CT (HRCT). The clinical and pathological spectrum is wide — from spontaneously resolving hypersensitivity pneumonitis to relentlessly progressive idiopathic pulmonary fibrosis (IPF) with a median survival of 3-5 years from diagnosis. IPF is the most common and most lethal idiopathic ILD, affecting predominantly men above age 60 with a smoking history; the characteristic UIP (usual interstitial pneumonia) pattern on HRCT — basal-predominant honeycombing with traction bronchiectasis — is highly diagnostic. ILD associated with connective tissue diseases (CTD-ILD) — systemic sclerosis, rheumatoid arthritis, myositis, Sjögren's syndrome — has a generally better prognosis and responds to immunosuppressive therapy. Accurate ILD classification requires multidisciplinary team (MDT) discussion combining clinical, radiological, and pathological information — the ILD-MDT model is now the global standard of care.

ILD has four major aetiological categories: Idiopathic interstitial pneumonias (IIPs): no identifiable cause; classified by clinical-radiological-pathological pattern. Idiopathic pulmonary fibrosis (IPF — UIP pattern): the most common IIP and most severe — predominantly affects men above 60 with significant smoking history; characterised by irreversible progressive fibrosis; BMPR2 mutations (familial IPF); MUC5B promoter polymorphism (the strongest genetic risk factor for IPF — increases risk 6-9-fold). Non-specific interstitial pneumonia (NSIP): a common CTD-ILD pattern; bilateral ground-glass opacities and reticulation with subpleural sparing; responds to corticosteroids and immunosuppression. Cryptogenic organising pneumonia (COP): consolidation, typically bilateral; responds well to corticosteroids. Desquamative interstitial pneumonia (DIP) and respiratory bronchiolitis-ILD (RB-ILD): smoking-related. Lymphoid interstitial pneumonia (LIP): associated with Sjögren's and HIV. ILD associated with connective tissue diseases (CTD-ILD): systemic sclerosis (the most common CTD-ILD — 75-90% of SSc patients have ILD on HRCT; NSIP pattern predominates; anti-Scl-70 antibody is a major risk factor); rheumatoid arthritis (RA-ILD — UIP or NSIP pattern; anti-CCP positive RA, male sex, and smoking are risk factors); inflammatory myopathies (dermatomyositis and polymyositis — NSIP or COP pattern; anti-MDA5, anti-Jo-1, anti-PL-7, anti-PL-12 antibodies identify ILD risk; anti-MDA5 associated with rapidly progressive ILD and high mortality); Sjögren's syndrome; SLE; mixed connective tissue disease. Hypersensitivity pneumonitis (HP — extrinsic allergic alveolitis): immune-mediated inflammatory response to repeated inhalation of organic antigens — bird fancier's lung (avian proteins from pigeons, parrots, budgerigars — the most common HP in the UK); farmer's lung (fungal spores from mouldy hay — Saccharopolyspora rectivirgula — thermophilic actinomycetes); mushroom worker's lung; hot tub lung (Mycobacterium avium complex); humidifier lung; and isocyanate exposure (painter's HP). Acute HP resolves on antigen removal; chronic HP can progress to fibrosis. Occupational and environmental ILD: pneumoconiosis — silicosis (crystalline silica dust — mining, quarrying, sandblasting; accelerated silicosis from high-intensity exposure); coal workers' pneumoconiosis (CWP); asbestosis (asbestos fibres — requires prolonged heavy exposure; ILD combined with pleural plaques, mesothelioma risk); berylliosis; drug-induced ILD (nitrofurantoin, amiodarone, bleomycin, methotrexate, checkpoint inhibitors — pembrolizumab, nivolumab causing immune pneumonitis in 5-15%). Sarcoidosis (granulomatous ILD): bilateral hilar lymphadenopathy, pulmonary infiltrates, and extrapulmonary involvement; elevated serum ACE.

The cardinal presenting symptom of ILD is progressive dyspnoea on exertion — typically insidious in onset (months to years in most ILDs; weeks in organising pneumonia; days in acute HP or acute exacerbation of IPF). Dry, persistent, non-productive cough — a hallmark symptom, particularly in IPF; may be the only symptom for months before dyspnoea develops. Fatigue and reduced exercise tolerance (progressive loss of cardiorespiratory reserve). Constitutional symptoms (fever, weight loss, malaise): particularly in hypersensitivity pneumonitis, organising pneumonia, and inflammatory CTD-ILD. Arthralgias, Raynaud's phenomenon, skin rash, sicca symptoms: suggest underlying CTD as the cause of ILD. Physical examination: fine end-inspiratory bibasal crepitations ('Velcro crackles' — the most characteristic auscultatory finding; present in 80%+ of IPF and other fibrotic ILDs; occasionally mistaken for heart failure crepitations — but ILD crackles are fine and dry rather than coarse and wet); digital clubbing (present in approximately 50% of IPF — indicates advanced fibrosis; rarely in other ILDs); peripheral cyanosis in advanced disease; signs of pulmonary hypertension (raised JVP, loud P2, RV heave — indicates severe functional impairment and predicts worse prognosis); features of underlying CTD: rash of dermatomyositis (heliotrope rash, Gottron's papules over knuckles), mechanic's hands (skin fissuring over fingers in anti-synthetase syndrome), sclerodactyly and telangiectasia (scleroderma), rheumatoid hands. Acute exacerbation of IPF: sudden acceleration of dyspnoea over days to weeks with bilateral new ground-glass opacities on CT superimposed on pre-existing UIP pattern fibrosis — triggers include infection, aspiration, surgery, and idiopathic; mortality 50-80%.

Multidisciplinary team (MDT) discussion combining clinical, radiology, and pathology is the gold standard for ILD diagnosis — no single test is sufficient. Pulmonary function tests (PFTs): spirometry — restrictive pattern (reduced FVC, reduced TLC with preserved or elevated FEV1/FVC ratio) characterises fibrosing ILD; obstructive or mixed pattern may occur in HP and sarcoidosis; FVC is the primary surrogate endpoint in clinical trials and serial monitoring. DLCO (diffusing capacity for carbon monoxide): reduced out of proportion to spirometric impairment — the most sensitive marker of ILD severity and gas exchange impairment; correlates with exercise oxygen desaturation and prognosis. Arterial blood gas or exercise oximetry: desaturation during the 6-minute walk test — SpO2 fall to below 88% indicates significant gas exchange impairment and qualifies for ambulatory supplemental oxygen. High-resolution CT chest (HRCT — thin-slice 1mm cuts, inspiratory and expiratory): the cornerstone of ILD diagnosis — pattern recognition is key; UIP pattern for IPF (bilateral, basal, subpleural honeycombing with or without traction bronchiectasis — 'definite UIP' on HRCT has 90%+ specificity for IPF, eliminating need for surgical biopsy in appropriate clinical context); NSIP pattern (bilateral ground-glass opacities and reticulation with subpleural sparing, no honeycombing — most common in CTD-ILD); organising pneumonia pattern (bilateral subpleural or peribronchial consolidation); hypersensitivity pneumonitis (bilateral upper and mid-zone ground-glass opacities, mosaic attenuation from air-trapping, centrilobular nodules — in acute/subacute HP; fibrotic changes in chronic HP). Serological testing: autoimmune panel (ANA, anti-dsDNA, anti-CCP, RF, anti-Scl-70, anti-centromere, anti-Jo-1 and anti-synthetase antibodies, anti-MDA5 — for CTD-ILD); serum ACE and calcium (sarcoidosis); Aspergillus and avian precipitins (HP); ANCA; anti-GBM. Bronchoalveolar lavage (BAL — flexible bronchoscopy): cell differential analysis — increased lymphocytes (HP, NSIP, sarcoidosis, COP); increased eosinophils (eosinophilic pneumonia, drug-induced ILD); increased neutrophils (IPF, bacterial infection). Microbiological culture and PCR for infectious causes. Transbronchial cryobiopsy (TBLC) or surgical lung biopsy (VATS — video-assisted thoracoscopic surgery): histopathological diagnosis when HRCT pattern is indeterminate or diagnosis is uncertain after full clinical and radiological assessment; cryobiopsy achieves diagnostic yield of 75-80% with lower morbidity than surgical biopsy; UIP histology (fibroblastic foci, temporal heterogeneity, honeycombing); NSIP histology (uniform temporal appearance, ground-glass predominance); HP histology (poorly formed granulomas, peribronchial fibrosis). 6-minute walk test (6MWT): functional assessment, exercise desaturation, prognostic value; baseline and serial monitoring.

Treatment is entirely guided by ILD subtype. Idiopathic pulmonary fibrosis (IPF): antifibrotic therapy is the standard of care for all patients with IPF, regardless of disease severity. Nintedanib (Ofev) 150 mg twice daily: tyrosine kinase inhibitor targeting VEGFR, FGFR, and PDGFRβ — reduces annual FVC decline by approximately 50% vs. placebo (INPULSIS trials); common side effects: diarrhoea (61%), nausea, LFT elevation (monitor LFTs monthly for 3 months then quarterly); dose reduction to 100 mg BD if not tolerated. Pirfenidone (Esbriet) 2403 mg/day in three divided doses with food: antifibrotic and anti-inflammatory — reduces FVC decline by 50% vs. placebo (ASCEND, CAPACITY trials); common side effects: photosensitivity (strict sun protection required), GI intolerance, fatigue, rash. Both antifibrotics slow progression but do not reverse established fibrosis. Lung transplantation: the only potentially curative option for advanced IPF — considered for patients with FVC below 50%, DLCO below 40%, exercise desaturation, or rapid FVC decline above 10%/year; bilateral sequential lung transplantation is preferred over single-lung transplant; 5-year post-transplant survival approximately 50-55%. Referral to transplant centre should be considered early. Management of complications: supplemental oxygen for SpO2 below 92% at rest or during exertion (improves symptoms; evidence for mortality benefit limited); pulmonary rehabilitation (evidence of improved exercise capacity and quality of life); gastro-oesophageal reflux disease (GORD) management (PPIs and prokinetics — GORD is highly prevalent in IPF and may contribute to microaspiration-driven progression); antitussive therapy (gabapentin or low-dose morphine for distressing cough); palliation for end-stage IPF. Connective tissue disease-associated ILD (CTD-ILD): immunosuppressive therapy is indicated for inflammatory CTD-ILD (NSIP, COP patterns). Mycophenolate mofetil (MMF — 2-3 g/day): the preferred first-line immunosuppressant for SSc-ILD (SLS II trial — equivalent to cyclophosphamide with better tolerability) and other CTD-ILD; well-tolerated. Rituximab (anti-CD20 — 1 g IV x2 doses 2 weeks apart): highly effective for myositis-associated ILD (anti-Jo-1, anti-MDA5) — recommended for refractory or severe rapidly progressive ILD. Cyclophosphamide (IV pulses or oral): for severe or rapidly progressive CTD-ILD — SSc-ILD, myositis-ILD (SLS I trial); second-line after MMF. Nintedanib (SSc-ILD — SENSCIS trial: reduced annual FVC decline by 44% vs. placebo; approved for SSc-ILD and other progressive fibrotic ILDs). Hypersensitivity pneumonitis: complete and permanent avoidance of the causative antigen is the most critical intervention — resolves acute HP; reduces progression of chronic HP. Corticosteroids (prednisolone 0.5-1 mg/kg/day tapered over 6-12 weeks) for acute and subacute HP and organising pneumonia. Immunosuppressants (mycophenolate, azathioprine) for chronic HP requiring long-term management. Sarcoidosis: corticosteroids for symptomatic pulmonary sarcoidosis (above stage II) or extra-pulmonary involvement; many cases resolve spontaneously.

Acute exacerbation of IPF (AE-IPF): a life-threatening acute acceleration of IPF — bilateral new ground-glass opacities on CT superimposed on pre-existing UIP fibrosis; triggered by occult infection (viruses, bacteria), aspiration, procedural (thoracic surgery), or idiopathic; characterised by worsening hypoxaemia, bilateral CT changes, and exclusion of heart failure, PE, or pneumonia; 30-day mortality 50-80%; treated with high-dose corticosteroids (1 g IV methylprednisolone daily for 3 days) empirical antimicrobials, and supportive care (supplemental oxygen, NIV, ICU); hospital acquired pneumonia is common. Pulmonary hypertension (PH-ILD — Group 3): develops in 30-40% of IPF patients; independent predictor of mortality; presents with worsening dyspnoea out of proportion to spirometric decline; echocardiography then right heart catheterisation for diagnosis; limited specific treatments for PH in ILD (PAH vasodilators generally not effective); supplemental oxygen; lung transplant consideration. Lung cancer: patients with IPF have an increased risk of lung cancer (prevalence 4-10% — from shared risk factors: smoking, male sex, older age, and potentially from fibrotic tissue transformation). Respiratory failure (type 1 — hypoxaemia): progressive gas exchange impairment leading to hypoxaemia at rest requiring supplemental oxygen; end-stage respiratory failure requiring mechanical ventilation (generally not recommended in IPF — poor outcomes; discussions around palliation and advance care planning are essential). Cor pulmonale and right heart failure: from chronic hypoxia and secondary pulmonary hypertension. Spontaneous pneumothorax: from rupture of subpleural honeycombing cysts — may be life-threatening in IPF due to limited pulmonary reserve. Psychological and quality of life impact: depression and anxiety affect over 40% of ILD patients; palliative care involvement from diagnosis is recommended to address symptom burden, breathlessness management, and end-of-life planning.

Smoking cessation is the most important preventive measure for smoking-related ILDs (IPF — smoking is the strongest modifiable risk factor; RB-ILD and DIP are directly caused by smoking and may improve with cessation; avoidance of passive smoke). Antigen avoidance is the cornerstone of hypersensitivity pneumonitis management — removal from the bird fancier environment, use of appropriate respiratory protective equipment in farming, adequate ventilation in indoor workplaces; high-efficiency particulate air (HEPA) filters reduce domestic antigen exposure. Occupational exposure protection: appropriate respiratory protective equipment (RPE) for silica (FFP3 respirators), asbestos (strict regulatory control — working with asbestos requires licensed contractor), coal dust, and isocyanates; regulatory occupational health surveillance for at-risk workers. Drug monitoring: drugs known to cause ILD (methotrexate, nitrofurantoin, amiodarone, bleomycin, checkpoint inhibitors) should be prescribed with awareness of ILD risk; baseline HRCT in patients starting checkpoint inhibitor immunotherapy; prompt investigation and drug discontinuation for new respiratory symptoms. CTD monitoring for ILD development: patients with systemic sclerosis, rheumatoid arthritis, and inflammatory myositis should have baseline HRCT, PFTs, and DLCO at diagnosis and at regular intervals (annually for high-risk patients) to detect subclinical ILD early — when treatment is most effective. Pulmonary rehabilitation: supervised multidisciplinary programme (exercise training, education, breathlessness management) improves exercise capacity, quality of life, and symptoms in all ILD subtypes; referral at diagnosis is recommended by BTS guidelines. Vaccination: annual influenza and pneumococcal vaccination for all ILD patients — respiratory infections precipitate acute exacerbations and accelerate decline. Advance care planning: early palliative care integration and honest prognostic communication about IPF (median survival 3-5 years) allows timely planning — preferred place of care and death, DNACPR decisions, and managing distressing breathlessness with opioids.

Go to A&E immediately for: sudden worsening breathlessness in a patient with known ILD (possible acute exacerbation, pneumothorax, pulmonary embolism, or pneumonia — all are medical emergencies in the context of limited pulmonary reserve); hypoxaemia (SpO2 persistently below 90%) with increasing breathlessness; and haemoptysis in an ILD patient (possible lung cancer, aspergilloma, or acute exacerbation). See a GP urgently (within 1-2 weeks) for: progressive unexplained breathlessness on exertion in an adult above 50 — particularly with bibasal crepitations on examination; unexplained persistent dry cough in a patient with a smoking history or connective tissue disease; and breathlessness in a patient known to have a connective tissue disease (possible CTD-ILD requiring specialist assessment). Any patient with known CTD (especially systemic sclerosis, RA, or inflammatory myositis) should have respiratory review and annual HRCT if at high risk. Refer urgently to a specialist ILD centre (within 2-4 weeks) for: newly diagnosed or suspected IPF — early antifibrotic therapy is associated with better outcomes; rapidly declining ILD (FVC fall above 10%/year) — requires therapy escalation, transplant assessment; and severe ILD with resting hypoxaemia — for oxygen assessment, transplant listing, and palliative care co-management.