Interstitial Lung Disease

Idiopathic Pulmonary Fibrosis

Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive fibrosing interstitial pneumonia of unknown cause, occurring predominantly in older adults, and defined histopathologically and/or radiologically by the pattern of usual interstitial pneumonia (UIP). It is the archetypal progressive fibrotic ILD and a high-yield MRCP topic because diagnosis requires integration of clinical context, HRCT pattern and exclusion of mimics, particularly connective tissue disease, chronic hypersensitivity pneumonitis and drug-related ILD.

Pathobiology and epidemiology

IPF is now conceptualised as an aberrant epithelial injury-repair disorder rather than a primarily inflammatory disease. Repetitive microinjury to ageing alveolar epithelium triggers epithelial apoptosis, impaired type II pneumocyte regeneration, fibroblast recruitment, myofibroblast differentiation and excessive extracellular matrix deposition. Key mediators include TGF-β, platelet-derived growth factor, fibroblast growth factor, vascular endothelial growth factor, lysophosphatidic acid and integrin-mediated activation of latent TGF-β. Genetic associations include MUC5B promoter polymorphism, telomerase mutations (TERT, TERC), surfactant protein mutations and familial pulmonary fibrosis syndromes.

Typical age is >60 years; IPF is uncommon below 50 years and should prompt reconsideration of familial disease, CTD-ILD or exposure-related ILD. Risk factors include male sex, cigarette smoking, chronic microaspiration/gastro-oesophageal reflux, metal/wood dust exposure and family history. Median untreated survival is approximately 3–5 years from diagnosis, but the course is heterogeneous: slow progression, stepwise decline, or acute exacerbations.

Clinical features and investigation

Patients present with insidious exertional dyspnoea and dry cough. Examination classically shows fine late-inspiratory bibasal “Velcro” crackles; digital clubbing occurs in approximately 25–50%. Pulmonary function tests usually demonstrate restriction with reduced TLC and FVC, and disproportionately impaired gas transfer. A fall in FVC ≥10% predicted or DLCO ≥15% predicted over 6–12 months is prognostically significant. Resting oxygen saturation may be preserved early; exertional desaturation on 6-minute walk testing is important prognostically.

Domain	Typical IPF finding	Exam-relevant implication
HRCT	Basal, subpleural reticulation; traction bronchiectasis; honeycombing; spatial and temporal heterogeneity	UIP pattern may obviate lung biopsy in correct clinical setting
PFTs	Reduced FVC/TLC, reduced DLCO; FEV1/FVC normal or high	Obstructive physiology suggests emphysema overlap, asthma/COPD or alternative diagnosis
Serology	ANA, RF, anti-CCP, ENA/myositis panel used to exclude CTD	Positive serology alone does not diagnose CTD-ILD; interpret with clinical phenotype
BAL	Not routine; may help exclude infection or HP	Lymphocytosis favours hypersensitivity pneumonitis over IPF

Diagnostic criteria and HRCT classification

Current ATS/ERS/JRS/ALAT guidance emphasises multidisciplinary discussion. IPF requires: compatible clinical syndrome, exclusion of known causes of ILD, and UIP/probable UIP on HRCT or histology where needed. Surgical lung biopsy or transbronchial lung cryobiopsy is considered when HRCT is indeterminate and the patient is fit enough; it is avoided when radiology is diagnostic or procedural risk is excessive.

HRCT category	Key features	Diagnostic consequence
UIP	Subpleural and basal predominant reticulation with honeycombing ± traction bronchiectasis	Diagnostic of IPF after exclusion of secondary causes
Probable UIP	Subpleural/basal reticulation with traction bronchiectasis but no honeycombing	Often sufficient for IPF in appropriate older patient after MDD
Indeterminate	Fibrosis without classic distribution or features	Consider biopsy/MDD; broaden differential
Alternative diagnosis	Upper/mid-zone predominance, peribronchovascular disease, nodules, mosaic attenuation, cysts, consolidation	Consider HP, sarcoid, CTD-ILD, drug toxicity, pneumoconiosis

Prognosis and staging

The GAP index is commonly used for mortality risk stratification. It incorporates gender, age, FVC and DLCO. Stage I has 1-year mortality around 6%, stage II around 16%, and stage III around 39%. Additional adverse markers include pulmonary hypertension, emphysema overlap, low or declining 6-minute walk distance, desaturation <88%, low DLCO, extensive honeycombing and acute exacerbation.

GAP variable	Score
Male sex	1
Age 61–65 / >65 years	1 / 2
FVC 50–75% / <50% predicted	1 / 2
DLCO 36–55% / ≤35% predicted or unable	1 / 2 or 3

Treatment

Management combines antifibrotic therapy, comorbidity optimisation, pulmonary rehabilitation, vaccination, oxygen assessment, advance care planning and early transplant referral where appropriate. Long-term corticosteroids, azathioprine and N-acetylcysteine combination therapy are harmful: the PANTHER-IPF trial was stopped early due to increased mortality and hospitalisation in the triple-therapy arm.

Drug	Dose	Mechanism and evidence	Important adverse effects/monitoring
Pirfenidone	Titrated to 801 mg three times daily orally; total 2403 mg/day	Antifibrotic, anti-TGF-β effects. ASCEND showed reduced proportion with ≥10% FVC decline or death at 52 weeks; pooled analyses suggest mortality benefit.	Nausea, dyspepsia, photosensitivity, rash, fatigue; monitor LFTs before treatment, monthly for 6 months, then 3-monthly.
Nintedanib	150 mg twice daily orally; reduce to 100 mg twice daily if intolerant	Tyrosine kinase inhibitor targeting VEGFR, FGFR, PDGFR. INPULSIS trials reduced annual FVC decline by approximately 50% versus placebo.	Diarrhoea, nausea, weight loss, hepatic enzyme elevation, bleeding risk; LFT monitoring as above, caution with anticoagulation.

NICE guidance supports antifibrotics for IPF with FVC generally between 50–80% predicted, with continuation dependent on tolerability and absence of marked progression; many contemporary pathways consider treatment beyond this range after specialist review. Acute exacerbation is defined by rapid respiratory deterioration, usually within <1 month, with new bilateral ground-glass opacities/consolidation superimposed on UIP not explained by cardiac failure or fluid overload. Management is supportive, excludes infection and pulmonary embolism, and often includes high-dose corticosteroids despite weak evidence.

Lung transplantation should be considered early in suitable patients, particularly age usually <65–70 years depending on centre, progressive disease despite therapy, DLCO <40%, oxygen requirement, pulmonary hypertension or hospitalisation for acute exacerbation. Pulmonary hypertension in IPF worsens prognosis; routine vasodilator therapy is not generally indicated outside selected specialist contexts.

Hypersensitivity Pneumonitis

Definition, antigens and immunopathogenesis

Hypersensitivity pneumonitis (HP), formerly extrinsic allergic alveolitis, is an immune-mediated interstitial lung disease caused by repeated inhalation of an inciting antigen in a susceptible host. Classic exposures include avian proteins (bird fancier’s lung), thermophilic actinomycetes in mouldy hay (farmer’s lung), contaminated humidifiers, metalworking fluids, isocyanates, and fungal antigens in domestic dampness. A careful exposure history is diagnostically pivotal: up to 40–60% of fibrotic HP cases have no antigen identified at presentation.

Pathogenesis combines type III immune-complex injury and type IV delayed hypersensitivity. Antigen deposition in terminal bronchioles and alveoli drives macrophage and T-cell activation, granulomatous inflammation, bronchiolocentric lymphocytic alveolitis, and, in chronic disease, fibroblast activation with architectural distortion. BAL typically demonstrates lymphocytosis; unlike sarcoidosis, the CD4:CD8 ratio is variable and is not diagnostically reliable.

Classification and clinical phenotypes

Modern guidelines classify HP as non-fibrotic or fibrotic, rather than acute/subacute/chronic, because fibrosis is the dominant prognostic determinant. Non-fibrotic HP may present hours after exposure with fever, malaise, cough, and dyspnoea, often improving on removal from exposure. Fibrotic HP presents insidiously with exertional dyspnoea, cough, inspiratory crackles, hypoxaemia, pulmonary hypertension, and clubbing less commonly than idiopathic pulmonary fibrosis (IPF).

Feature	Non-fibrotic HP	Fibrotic HP
Dominant pathology	Cellular bronchiolitis, lymphocytic alveolitis, poorly formed granulomas	Bronchiolocentric fibrosis, bridging fibrosis, sometimes UIP-like pattern
HRCT pattern	Ground-glass opacity, centrilobular nodules, mosaic attenuation	Reticulation, traction bronchiectasis, volume loss; upper/mid-zone or diffuse fibrosis common
Key clue	Temporal relationship to antigen exposure	Air-trapping/mosaic attenuation superimposed on fibrosis; exposure often occult
Prognosis	Often reversible with antigen avoidance	Variable; may progress like IPF if antigen persists or fibrosis established

Diagnosis: integrating exposure, HRCT, BAL and histology

The 2020 ATS/JRS/ALAT guideline recommends a multidisciplinary diagnosis using three domains: exposure identification, HRCT pattern, and BAL or histopathology. Diagnostic confidence is graded as definite, high-confidence, moderate-confidence, or low-confidence; no single test is definitive.

Serum antigen-specific IgG supports exposure rather than disease. It has moderate sensitivity and specificity, varying by antigen panel and population, and false positives occur in asymptomatic exposed individuals. It should not be used as a screening test in isolation.

HRCT should include inspiratory and expiratory acquisitions. The most exam-relevant sign is the three-density pattern—formerly “headcheese”—reflecting normal lung, ground-glass inflammation, and low-attenuation air-trapping from small-airways disease. Air-trapping on expiratory CT and ill-defined centrilobular nodules strongly favour HP over IPF. In fibrotic HP, fibrosis may mimic usual interstitial pneumonia, but profuse mosaic attenuation, lobular air-trapping, and relative upper/mid-zone predominance suggest HP.

Investigation	Typical finding	Exam caveat
BAL	Lymphocytosis; guideline threshold often >30% in suspected HP	Lower lymphocyte counts occur in fibrotic HP, smokers, and advanced disease
PFTs	Restrictive defect, reduced TLCO; obstructive or mixed pattern may occur due to bronchiolitis	TLCO is often the earliest abnormality and correlates with prognosis
Histology	Cellular bronchiolitis, bronchiolocentric interstitial pneumonia, poorly formed non-necrotising granulomas	Absence of granulomas does not exclude fibrotic HP
Blood tests	May show raised CRP/ESR in non-fibrotic flares	Peripheral eosinophilia suggests alternative diagnoses

Management

The cornerstone is complete antigen avoidance, including occupational assessment, home inspection for damp/mould, removal of birds/feather bedding, ventilation remediation, and respiratory protective equipment where avoidance is impossible. Continued exposure is associated with relapse, accelerated FVC decline, and mortality in fibrotic HP.

Corticosteroids hasten symptomatic and physiological recovery in inflammatory HP but have not convincingly altered long-term outcome once fibrosis is established. A common regimen is prednisolone 0.5 mg/kg/day orally for 2–4 weeks, followed by taper over 2–3 months according to symptoms, FVC, TLCO, oxygenation, and radiology. Longer courses increase infection, osteoporosis, diabetes, and myopathy risk and should prompt reassessment of diagnosis and exposure control.

Therapy	Typical adult dose	Role
Prednisolone	0.5 mg/kg/day initially, tapering over weeks to months	Symptomatic non-fibrotic HP or inflammatory exacerbation
Mycophenolate mofetil	500 mg twice daily increasing to 1–1.5 g twice daily	Steroid-sparing option in selected persistent inflammatory disease
Azathioprine	1–2 mg/kg/day after TPMT assessment	Alternative steroid-sparing agent; monitor FBC/LFTs
Nintedanib	150 mg twice daily	Progressive fibrosing HP phenotype despite standard management

For progressive pulmonary fibrosis, defined in recent guidance by worsening symptoms, physiological decline such as absolute FVC fall ≥5% predicted or TLCO fall ≥10% predicted within 1 year, and/or radiological progression, antifibrotic therapy should be considered. In the INBUILD trial, nintedanib reduced annual FVC decline in progressive fibrosing ILD from approximately −188 mL/year to −81 mL/year, with diarrhoea the commonest adverse effect. Lung transplantation referral is appropriate for advanced fibrotic HP with progressive decline, resting or exertional hypoxaemia, pulmonary hypertension, or recurrent acute deteriorations.

Pneumoconioses

Pneumoconioses are occupational interstitial lung diseases caused by inhalation and retention of inorganic dusts, with lung injury determined by particle size, cumulative dose, surface reactivity and host susceptibility. Respirable particles are typically <5 μm aerodynamic diameter and reach terminal bronchioles/alveoli; fibres are pathogenic when long, thin and biopersistent. Pathogenesis centres on macrophage phagocytosis, frustrated phagocytosis, inflammasome activation, reactive oxygen species, fibroblast recruitment and collagen deposition. The latency is usually long: 10–30 years for coal workers’ pneumoconiosis and asbestosis, but accelerated silicosis may occur after 5–10 years of high exposure and acute silicoproteinosis after months to a few years.

Major pneumoconioses: exam-relevant comparison

Condition	Exposure	Pathology and imaging	Key complications
Coal workers’ pneumoconiosis	Coal mining; risk increases with cumulative respirable coal mine dust and silica content	Coal macules around respiratory bronchioles; upper-zone small rounded opacities. Progressive massive fibrosis produces large upper-lobe conglomerate masses with emphysema and distortion.	Chronic bronchitis/COPD, progressive massive fibrosis, respiratory failure, pulmonary hypertension; Caplan syndrome with rheumatoid arthritis.
Silicosis	Mining, quarrying, tunnelling, foundries, sandblasting, stone countertop fabrication	Fibrotic silicotic nodules with concentric “onion-skin” collagen; upper-lobe nodules, eggshell hilar/mediastinal calcification; acute silicoproteinosis shows alveolar filling mimicking pulmonary alveolar proteinosis.	Tuberculosis and non-tuberculous mycobacteria, chronic kidney disease, autoimmune disease, lung cancer; progressive massive fibrosis.
Asbestosis	Shipyards, insulation, construction, brake linings; amphiboles more carcinogenic than chrysotile	Diffuse interstitial fibrosis beginning subpleurally in lower lobes; asbestos bodies. HRCT: basal subpleural reticulation, traction bronchiectasis, honeycombing; pleural plaques strongly indicate exposure but not necessarily asbestosis.	Lung cancer, malignant mesothelioma, benign pleural effusion, diffuse pleural thickening, rounded atelectasis.
Chronic beryllium disease	Aerospace, nuclear, electronics, ceramics	Immune granulomatous disease resembling sarcoidosis; BeLPT demonstrates beryllium sensitisation.	Progressive granulomatous ILD; distinguish from sarcoidosis by exposure history and beryllium lymphocyte proliferation testing.

Classification, staging and physiological assessment

The standard epidemiological radiographic system is the ILO International Classification of Radiographs of Pneumoconioses. Small opacity profusion is graded on a 12-point scale: 0/−, 0/0, 0/1; 1/0, 1/1, 1/2; 2/1, 2/2, 2/3; 3/2, 3/3, 3/+. Shape/size is recorded as rounded p, q, r or irregular s, t, u. Large opacities indicating progressive massive fibrosis are categories A (one or more opacities with combined diameter >10 mm but ≤50 mm), B (>50 mm but not exceeding the equivalent area of the right upper zone), and C (exceeding category B). HRCT is more sensitive than chest radiography for early disease, pleural plaques, rounded atelectasis and emphysema, but ILO remains important for surveillance and compensation.

Pulmonary function varies. Simple coal workers’ pneumoconiosis may have near-normal spirometry; emphysema causes obstruction. Asbestosis classically produces restriction with reduced transfer factor: FVC <80% predicted and DLCO <80% predicted are commonly used abnormal thresholds, but serial decline is more informative. Exercise desaturation and resting hypoxaemia imply advanced disease; oxygen is indicated using usual chronic respiratory failure criteria, for example PaO₂ ≤7.3 kPa or ≤8.0 kPa with pulmonary hypertension/polycythaemia, depending on local guidance.

Diagnostic approach

Diagnosis requires a compatible occupational history, sufficient latency and radiological pattern, with exclusion of alternative ILD. The exposure history must specify job tasks, duration, dust control, respiratory protection, co-workers affected and dates relative to symptoms. In suspected asbestosis, pleural plaques support exposure but fibrosis is required for the diagnosis; isolated plaques usually do not impair lung function. In silicosis, screen actively for tuberculosis: symptoms, chest imaging and microbiology when indicated. Tuberculin testing may be falsely negative in advanced disease; interferon-γ release assays are often used, although neither distinguishes latent from active infection.

Beryllium disease is an important MRCP discriminator: unlike sarcoidosis, it requires beryllium sensitisation demonstrated by abnormal blood or bronchoalveolar lavage beryllium lymphocyte proliferation test, plus compatible granulomatous lung disease. Serum ACE and hypercalcaemia are non-specific and should not be used to secure sarcoidosis if beryllium exposure is plausible.

Management and prevention

The cornerstone is exposure cessation or reduction; established fibrosis is usually irreversible. Smoking cessation is critical, particularly in asbestos-exposed workers because smoking and asbestos interact multiplicatively for lung cancer risk. Pharmacological anti-fibrotic therapy is not established for classical pneumoconioses, although progressive fibrosing phenotypes may be considered under broader progressive pulmonary fibrosis guidance in specialist ILD centres. Corticosteroids are not useful for simple coal workers’ pneumoconiosis, silicosis or asbestosis; they may be used in chronic beryllium disease with functional impairment, commonly prednisolone 20–40 mg daily initially with taper to the lowest effective dose, and steroid-sparing immunosuppression in selected cases.

• Supportive care: vaccination against influenza and pneumococcus, pulmonary rehabilitation, ambulatory/long-term oxygen when criteria are met, treatment of airflow obstruction, and assessment for pulmonary hypertension in disproportionate dyspnoea.
• Silicosis: maintain a low threshold for TB investigation and treatment; progressive massive fibrosis may progress despite exposure removal.
• Asbestos: investigate new pleural effusion, unilateral pleural thickening, chest pain or weight loss for mesothelioma; pleural plaques alone require reassurance and exposure documentation rather than treatment.
• Advanced disease: refer early for lung transplantation assessment when severe physiological impairment, progressive hypoxaemia or pulmonary hypertension develops.

Prevention is regulatory and engineering-led: substitution, wet cutting, enclosure, local exhaust ventilation, respirator fit-testing and medical surveillance. Common occupational exposure limits include respirable crystalline silica around 0.05 mg/m³ as an 8-hour time-weighted average in several jurisdictions, and asbestos exposure should be as low as reasonably practicable with stringent control because no safe carcinogenic threshold is accepted. For exam purposes, never diagnose “idiopathic” pulmonary fibrosis without first excluding pneumoconiosis by a meticulous lifetime occupational history.