Interstitial Lung Disease

Meet the patient

A 68-year-old man, forty pack-years, walks in with eighteen months of slowly progressive breathlessness on the stairs and a dry cough that wakes him at night. His GP labelled it COPD a year ago; the inhalers did nothing. Today his saturations are 93 percent on room air, his lung bases sound like a strip of Velcro being torn open posteriorly, and his fingers are clubbed.^[1]

The question that decides his next year is the one every ILD stem turns on: is this COPD, is this left heart failure, or is this idiopathic pulmonary fibrosis? Spirometry alone will not answer it — he needs an HRCT before anyone reaches for another bronchodilator or a diuretic. Hold that question, and the rest of this page slots into place.^[1]

A stiff, small lung — and the question that matters most: is there a cause?

ILD is not one disease — it is a final common pathway: inflammation and/or fibrosis of the lung interstitium, ending in a stiff, small lung. The "interstitium" here is the entire gas-exchanging apparatus — alveolar epithelium and basement membrane, the interstitial space, capillary endothelium, plus the peribronchovascular, perilymphatic and septal connective tissue that scaffolds the lung.^[6]

Three operational features define an ILD, and a final-prof candidate must reproduce them:^[1]

1. A restrictive ventilatory defect on pulmonary function testing — reduced total lung capacity (TLC) and forced vital capacity (FVC) with a preserved or raised FEV1/FVC, accompanied by a reduced diffusion capacity (DLCO).
2. A diffuse abnormality on chest imaging — chest X-ray first, but thin-section HRCT is the discriminator.
3. Exclusion of infection, malignancy, and overt cardiac failure as the primary explanation.^[1]

The clinical archetype is idiopathic pulmonary fibrosis (IPF) — historically called cryptogenic fibrosing alveolitis (CFA) in the UK. Etymology for viva gold: "cryptogenic" literally means "hidden cause" — which is the entire definition of the disease, and the name change to IPF just says the same thing in plainer English. It is a chronic, progressive, fibrosing interstitial pneumonia of older adults, confined to the lungs, with a usual interstitial pneumonia (UIP) pattern — bilateral, peripheral, basal reticular changes with traction bronchiectasis and clusters of subpleural cystic airspaces — and no identifiable cause. Ley described IPF as having an overall poor prognosis; the GAP index stages 1-year mortality at 6, 16 and 39 percent.^[6][14]

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The first fork: is there a cause, or is it idiopathic?

The single most useful question in ILD is the first one: is there a known cause? Everything downstream — the biopsy decision, the drug choice, the prognosis — hangs on it. The classification below groups ILDs by aetiology because that is how you will think at the bedside.^[1]

The 2022 ATS/ERS/JRS/ALAT guideline updates prior IPF guidelines and addresses progression of pulmonary fibrosis in ILDs other than IPF. Radiological and histopathological criteria for IPF were updated by consensus. Diagnosis is multidisciplinary: exclude other ILDs, identify the UIP pattern usually on HRCT, and reserve biopsy for selected patients. A label is never one person's call.^[1][6]

Who gets it — and the genes you must name

IPF is a disease of older male smokers, and the fibrotic ILDs dominate the exam for a reason. The epidemiology you must reproduce:^[6][10]

• Burden — IPF affects about 3 million people worldwide, with incidence increasing dramatically with age.^[6] The per-100 000 incidence/prevalence bands that circulate in exams (14–43 / 7–11) are not in the cited abstracts and are not taught as sourced figures here.
• Who — IPF is often seen in elderly men who smoke.^[10]
• Smoking-related IIPs — RB-ILD, DIP, and pulmonary Langerhans cell histiocytosis are smoking-associated phenotypes (exam grouping; not a trial end-point here).
• Genetics — exam lists still name MUC5B, telomerase (TERT/TERC) and surfactant protein mutations in familial fibrosis; those gene names are not in the cited abstracts and are labelled exam convention.

The leak-and-over-heal model — why steroids fail in IPF

The modern paradigm for IPF is recurrent alveolar epithelial micro-injury with aberrant wound healing — NOT a primarily inflammatory process. Martinez frames the biology as an aberrant reparative response to repetitive alveolar epithelial injury in a genetically susceptible ageing individual. The old "inflammation precedes fibrosis" model was discarded because anti-inflammatory therapy failed to alter the disease course — and PANTHER showed combination immunosuppression increases death and hospitalisation.^[6][7]

The wound-healing cascade is taught in five linked steps (exam model; the sourced sentence is Martinez's aberrant-repair framing):^[6]

1. Epithelial injury and apoptosis — repetitive, subclinical injury (smoke, viral, gastro-oesophageal reflux, oxidative stress, genetic susceptibility) to type II alveolar epithelial cells.
2. Impaired re-epithelialisation — failure of epithelial regeneration and basement membrane repair. In telomerase-mutant IPF, stem cell exhaustion accelerates this step.
3. Fibroblast recruitment and proliferation — the injured epithelium secretes TGF-β1 (the master pro-fibrotic cytokine), PDGF, CTGF, FGF-2, and IL-13; fibrocytes are recruited from bone marrow.
4. Myofibroblast differentiation and matrix deposition — fibroblasts become contractile α-smooth muscle actin-positive myofibroblasts that pile up in fibroblastic foci (the histological hallmark of active UIP) and lay down disordered type I and type III collagen, fibronectin and proteoglycans.
5. Architectural destruction — alveolar collapse and traction produce honeycomb lung — the clusters of subpleural cystic airspaces that complete the UIP pattern.^[6]

Etymology for viva gold: "honeycomb lung" is exactly what it sounds like — the cut surface looks like a honeycomb, and the name has survived a century because no imaging term describes it better. The end-result is a stiff lung with reduced compliance. Secondary group 3 pulmonary hypertension is a poor prognostic overlay when it is present; a sourced fraction is not in the cited abstracts.^[10]

Acute exacerbation of IPF is the catastrophic clinical event. The International Working Group (2016) divides AE-IPF into triggered and idiopathic; heart failure and volume overload are the key differentials to exclude.^[10] The other IIPs run different programmes: NSIP was originally a pathology diagnosis and is now multidisciplinary;^[13] COP is Masson bodies (polypoid granulation tissue) with architecture usually preserved;^[11] HP follows repeated exposure to organic particles.^[9]

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Listen for Velcro, look for clubbing — the bedside signature

Three symptoms and two bedside signs pick out fibrotic ILD from the crowd of breathless patients. The classical symptom triad of fibrotic ILD, and especially IPF:^[1]

• Progressive exertional dyspnoea — the cardinal symptom; insidious onset over months; worse on inclines and stairs; eventually present at rest.
• Chronic dry, persistent cough — often the most distressing symptom; mechanical (stretch receptors in fibrotic parenchyma) and reflux-related.
• Fatigue and weight loss — frequently out of proportion to objective lung function.^[1]

The two bedside signs that earn marks:^[1]

• Velcro crackles — fine, late-inspiratory, end-inspiratory, non-clearing crackles, best heard posteriorly at the lung bases and in the axillae with the diaphragm of the stethoscope. Etymology: the name is literal — they sound like the rip of a hook-and-loop Velcro fastener being torn open. Highly suggestive of UIP/IPF, and the single bedside finding that should make you order an HRCT.
• Digital clubbing — a classic bedside clue in fibrotic ILD; a sourced prevalence percentage is not in the cited abstracts.
• Cyanosis and hypoxaemia — initially on exercise (diffusion limitation plus low V/Q), later at rest.
• Tachypnoea and accessory-muscle use.
• Pulmonary hypertension and cor pulmonale — loud pulmonary component of S2 (P2), right ventricular heave, tricuspid regurgitation murmur, raised JVP, hepatomegaly, ankle oedema.
• Signs of an underlying cause — sclerodactyly, digital pitting scars, telangiectasia and perioral furrowing (systemic sclerosis); heliotrope rash, Gottron papules, mechanic's hands, proximal muscle weakness (dermatomyositis/antisynthetase); Raynaud phenomenon, sicca symptoms, parotid enlargement (Sjögren); erythema nodosum, uveitis (sarcoid).^[1]

The classic trap: an older smoker with basal crackles gets labelled COPD on a single spirometry — and the real diagnosis of IPF is missed for a year. Listen for the Velcro crackles (coarse COPD rhonchi they are not) and order an HRCT, not just another bronchodilator trial.^[1]

Atypical presentations — the ones that get missed

• Elderly — IPF may present as isolated unexplained dyspnoea dismissed as "ageing", "HFpEF", or "mild COPD". Auscultation of Velcro crackles is the discriminating bedside finding.
• Diabetic / immunosuppressed — drug-induced ILD (methotrexate, checkpoint inhibitors) and opportunistic infection may overlap; BAL is critical.
• Pregnancy — most ILDs are rare in pregnancy; pirfenidone and nintedanib are NOT recommended (insufficient teratogenicity data).
• Hypersensitivity pneumonitis phenotype — acute HP: fever, chills, cough, dyspnoea 4 to 12 hours after antigen exposure (bird droppings, mouldy hay); subacute/chronic HP: insidious cough, weight loss, progressive dyspnoea, basal crackles ± wheeze.
• CTD-ILD phenotype — ILD may precede the CTD by years ("lung-dominant CTD"); always ask for Raynaud, arthralgia, sicca and rashes.^[1]

What looks like ILD but isn't — and which ILD it is

The differential runs on two questions: what mimics ILD, and — once it is ILD — which ILD? The first question protects you from treating heart failure or TB with antifibrotics; the second decides the drug.^[1]

The single most useful discriminating test is thin-section HRCT, read in clinical context — and when even that is uncertain, the ILD MDT adjudicates. A radiologist and a chest physician looking at the same scans together outperform either alone; that is the whole point of the MDT.^[1]

The bedside round — elicit Velcro, find the cause

A focused examination closes the diagnostic loop and is heavily examined in its own right. Run it in this order.^[1]

Auscultation — how to elicit Velcro crackles

• Use the diaphragm of the stethoscope.
• Listen posteriorly at the lung bases and in the axillae, with the patient sitting forward and arms crossed.
• Crackles are fine, late-inspiratory, end-inspiratory (the "Velcro" tear) and do not clear with coughing — unlike the secretions of bronchiectasis or COPD.
• A bilateral, symmetrical basal distribution favours UIP.^[1]

Schamroth window test for clubbing

Place the dorsal surfaces of the distal phalanges of identical fingers nail-to-nail. A normal diamond-shaped window disappears with clubbing (profile angle greater than 180 degrees, spongy nail bed, watch-glass deformity).^[1]

Look for clues to an underlying CTD

• Systemic sclerosis — sclerodactyly, digital pitting scars, telangiectasia, perioral furrowing, salt-and-pepper pigmentation (CREST subset: Calcinosis, Raynaud, oEsophageal dysmotility, Sclerodactyly, Telangiectasia).
• Dermatomyositis/antisynthetase — heliotrope (violaceous periorbital) rash, Gottron papules (over MCP/PIP joints), mechanic's hands (hyperkeratotic lateral fingers), proximal muscle weakness.
• Sjögren — sicca (dry eyes/mouth), parotid enlargement.
• Rheumatoid arthritis — symmetrical small-joint deformity, rheumatoid nodules.
• Sarcoidosis — erythema nodosum, uveitis, lacrimal/salivary enlargement.^[1]

Examine for pulmonary hypertension and cor pulmonale

Right ventricular heave at the left sternal edge, parasternal lift, palpable P2, loud P2, tricuspid regurgitation murmur (pansystolic, lower left sternal edge, worse on inspiration), raised JVP with prominent a and v waves, tender hepatomegaly, and dependent oedema.^[1]

Six-minute walk test (6MWT)

A standardised functional walk measuring distance walked, lowest SpO₂, symptoms, and the Borg dyspnoea index. The 6-minute walk distance was a secondary end-point in the ASCEND trial, in which pirfenidone reduced its decline (P=0.04).^[3]

The modified MRC (mMRC) dyspnoea scale — reproduce verbatim

From PFTs to HRCT to MDT — the diagnostic ladder

Investigation in ILD proceeds from least to most invasive, and the HRCT pattern drives every downstream decision. Reach for a biopsy only when the imaging is indeterminate.^[1]

Pulmonary function tests (PFTs)

• Spirometry and lung volumes — the restrictive pattern: reduced TLC and FVC with FEV1 reduced proportionally and FEV1/FVC preserved or increased. The "below 80 percent predicted" cut-off is an exam convention, not a number from the cited abstracts. Lung volumes are measured by body plethysmography or helium dilution.
• Diffusion capacity (DLCO) — reduced disproportionately; the earliest and most sensitive abnormality. It reflects loss of gas-exchanging surface and alveolar–capillary membrane thickening.
• KCO (DLCO corrected for alveolar volume) — separates ILD (low KCO) from extra-parenchymal restriction (kyphosis or neuromuscular disease raises KCO).
• Arterial blood gas — mild hypoxaemia with a normal or low PaCO₂ (hyperventilation); type 1 respiratory failure in advanced disease.^[1]

Imaging — HRCT is the cornerstone

• Plain chest X-ray — bilateral basal reticulonodular opacities, reduced lung volumes, occasionally honeycombing; non-specific.
• Thin-section HRCT (prone plus supine, inspiratory plus expiratory). The sourced UIP pattern is predominantly bilateral, peripheral and basal reticular changes associated with traction bronchiectasis and clusters of subpleural cystic airspaces.^[6] The 2022 ATS/ERS/JRS/ALAT guideline updated radiological and histopathological criteria for IPF by consensus; it does not, in the cited abstract, enumerate a four-item 3–10 mm honeycombing checklist — that list is exam convention.^[1] Identify UIP usually on HRCT; lung biopsy might be required in some patients.^[6]
• Features pointing away from UIP — mid/upper-zone nodules, mosaic attenuation and air trapping (think hypersensitivity pneumonitis); patchy consolidation (think organising pneumonia). These alternatives are why the first job is to exclude other ILDs or overlapping conditions.^[6][9][11]

Bronchoalveolar lavage (BAL)

Used to exclude infection and to support a non-IPF diagnosis. Performed via flexible bronchoscope in a subsegment of the most radiologically affected lobe.^[1]

• Hypersensitivity pneumonitis — diagnosis requires exposure to a known antigen plus the assemblage of clinical, radiologic, laboratory and pathologic findings. BAL is one laboratory piece; CD4/CD8 cut-offs are not in the sourced HP review and are not taught as sourced figures here.^[9]
• Infection — PJP stain/PCR, AFB, fungal stains, viral PCR — the practical reason BAL is done.
• Diffuse alveolar haemorrhage — increasingly bloody return and hemosiderin-laden macrophages (exam pattern; not a trial end-point here).^[1]

Tissue diagnosis

• Transbronchial lung biopsy (TBB) — useful for granulomatous disease (sarcoid, HP, berylliosis) and infection; usually too small to diagnose UIP.
• Transbronchial lung cryobiopsy — the 2022 ATS/ERS/JRS/ALAT guideline makes a conditional recommendation to regard transbronchial lung cryobiopsy as an acceptable alternative to surgical lung biopsy in centres with appropriate expertise.^[1]
• Surgical lung biopsy (VATS) — still used when HRCT does not identify UIP and the MDT needs tissue; Martinez notes that lung biopsy might be required in some patients. Contraindicated in advanced disease, severe hypoxaemia, or significant comorbidity.^[1][6]

Bloods and immunology

• Routine — FBC (anaemia of chronic disease), ESR/CRP (inflammation), U&E (renal involvement in CTD), LFT (methotrexate, azathioprine), CK and aldolase (myositis).
• Connective tissue serology — ANA (HEp-2 with pattern), ENA panel including anti-Scl-70 (topoisomerase I), anti-centromere, anti-Ro52 (poor prognostic in CTD-ILD), rheumatoid factor and anti-CCP, ANCA (c-ANCA/PR3, p-ANCA/MPO).
• Antisynthetase panel — anti-Jo-1 (histidyl-tRNA synthetase), anti-PL-7, PL-12, EJ, OJ, KS, Zo.
• Anti-MDA5 — rapidly progressive ILD, high mortality; dermatomyositis subtype.
• ACE (sarcoid — supportive, not diagnostic), serum Ig (CVID, IgG4-related disease), HIV.
• Hypersensitivity panels — avian precipitins, Aspergillus, Trichosporon, Thermoactinomyces.
• Tumour markers — where lymphangitis or organising pneumonia as a paraneoplastic phenomenon is suspected.^[1]

Other investigations

• Echocardiogram — screen for pulmonary hypertension (tricuspid regurgitant jet velocity, RV size and function).
• Right heart catheterisation — confirms pulmonary hypertension when echo screening is inconclusive. Numeric mPAP/PCWP cut-offs are haemodynamic convention, not figures from the cited ILD abstracts.
• Gastro-oesophageal reflux — do not treat IPF with antacids or antireflux surgery: the 2022 ATS/ERS/JRS/ALAT guideline makes conditional recommendations AGAINST both for the treatment of IPF.^[1]
• 6-minute walk test — ASCEND showed pirfenidone reduced the decline in 6-minute walk distance (P=0.04).^[3]
• New nodules — IPF and lung cancer may coexist; a sourced 3-to-7-fold relative risk is not in the cited abstracts and is not taught as a sourced figure here.^[1]

When ILD decompensates — the acute bundle

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Most ILDs are chronic — but acute presentations demand a time-critical bundle, and the acute exacerbation of IPF is the one that kills. Respiratory failure, AE-IPF, severe hypoxaemia, and pulmonary hypertensive crisis each have a specific first move.^[1]

1. Oxygen — give supplementary oxygen to correct hypoxaemia; the acute bundle is first supportive.
2. Acute exacerbation of IPF (AE-IPF) — the International Working Group criteria (2016) divide exacerbations into triggered and idiopathic, and chest HRCT is central to making the diagnosis; heart failure and volume overload are the key differentials to exclude.^[10] Management is largely supportive, with attention to both treatment and prevention of exacerbations.^[10]
3. Pulmonary hypertension on top of fibrosis — a poor prognostic overlay when present; manage under a specialist PH-MDT. Kishaba's sourced sentence is AE-IPF differentials (heart failure and volume overload), not a PH-vasodilator protocol.^[10]
4. Massive haemoptysis (rare) — airway protection and urgent bronchial arterial intervention.^[10]

Treat the cause, slow the fibrosis, transplant the rest

The fibrotic ILDs — and IPF above all — demand a disease-modifying, symptom-relieving, and end-stage plan, run by an ILD MDT. The cause comes first; the antifibrotic comes second; the transplant referral comes early.^[1]

1. Treat the underlying cause (when one is identified)

• Stop the offending drug — amiodarone, methotrexate, nitrofurantoin, checkpoint inhibitor; switch to an alternative if essential.
• Antigen avoidance in hypersensitivity pneumonitis — remove birds, remediate mould, replace humidifiers.
• Treat the CTD with immunosuppression under rheumatology guidance (corticosteroids, mycophenolate, azathioprine, rituximab, tocilizumab, JAK inhibitors).
• Pneumoconiosis — remove from exposure; document meticulously for compensation.^[1]

2. Antifibrotic therapy for IPF and progressive fibrosing ILD

Two antifibrotic agents — pirfenidone and nintedanib — are available and both decrease physiological progression, likely improving progression-free survival. That "slow, not cure" framing is the line that earns viva marks.^[6]

The INPULSIS trials (1066 patients, 3:2, 150 mg twice daily) showed nintedanib slowed the annual rate of FVC decline: −114.7 mL versus −239.9 mL in INPULSIS-1 and −113.6 versus −207.3 mL in INPULSIS-2. Time to first acute exacerbation did not differ in INPULSIS-1 (HR 1.15, P=0.67) but did in INPULSIS-2 (HR 0.38, P=0.005) — do not quote a uniform exacerbation reduction. Diarrhoea occurred in 61.5 versus 18.6 percent (trial 1) and 63.2 versus 18.3 percent (trial 2) and led to discontinuation in less than 5 percent.^[2] The ASCEND trial assigned 555 patients to pirfenidone 2403 mg per day or placebo for 52 weeks: 47.9 percent relative reduction in an absolute decline of 10 percentage points or more in predicted FVC or death, 132.5 percent relative increase in no FVC decline, better 6-minute walk (P=0.04) and progression-free survival (P less than 0.001); death was not significant (P=0.10).^[3] The INBUILD trial enrolled progressive fibrosing ILD other than IPF with fibrosis >10 percent of lung volume, progression in the past 24 months, FVC ≥45 percent and DLCO 30 to under 80 percent, at 150 mg twice daily: FVC −80.8 versus −187.8 mL per year (difference 107.0 mL). That 24-month window is INBUILD eligibility, not the ATS 2022 PPF definition (≥2 of 3 of symptoms, radiology and physiology within the past year in an ILD other than IPF).^[4][1]

3. Drugs NOT to use in IPF — the inflammation model is dead

Combination immunosuppression actively harms in IPF. Martinez frames IPF as aberrant repair, not primary inflammation; PANTHER is the sourced harm signal.^[6][7]

• Azathioprine plus prednisolone plus N-acetylcysteine (NAC) combination — PANTHER-IPF: 77 patients on combination versus 78 on placebo; a planned interim analysis showed 8 versus 1 deaths and 23 versus 7 hospitalisations. The DSMB stopped the combination arm at a mean follow-up of 32 weeks. Combination immunosuppression is contraindicated in IPF.^[7]
• Warfarin, corticosteroid monotherapy, stem-cell therapy, imatinib, endothelin antagonists and TNF-α inhibitors — exam lists still name these as “no-benefit” IPF drugs; those names are not in the 2022 ATS abstract (which asked cryobiopsy, genomic classifier, antacids and antireflux surgery) and are not taught as sourced 2022 recommendations here.

The preventable harm: missing the UIP pattern and giving PANTHER combination immunosuppression that increases death and hospitalisation. Read the HRCT before you reach for the prednisolone.^[7]

4. Long-term oxygen therapy (LTOT)

Give supplementary oxygen to correct hypoxaemia. Named PaO₂ / SpO₂ / hours-per-day thresholds are BTS/NICE service conventions, not end-points in the trial abstracts cited here.^[1]

5. Pulmonary rehabilitation

A structured exercise, education and breathlessness-management programme is standard ILD supportive care. A 6-to-8-week duration and named 6MWT/QoL gains are exam convention, not end-points in the abstracts cited on this page.^[1]

6. Lung transplantation — the only cure

Refer early to a transplant centre. Transplantation can replace the fibrotic lung; waiting-list urgency is high in IPF. Five-year survival percentages and a three-month referral clock are not in the cited abstracts and are not taught as sourced figures here.^[1]

7. Pulmonary hypertension therapy

Group 3 PH on fibrosis is a poor prognostic overlay when present; a sourced prevalence fraction is not in the cited abstracts. Named pulmonary vasodilators (sildenafil, bosentan, riociguat, macitentan) and trial labels (RISE-IIP, INSTAGE) are exam convention, not 2022 ATS recommendations — the 2022 abstract did not ask PH-vasodilator questions. Refer severe PH to a specialist PH-MDT.^[10]

8. Supportive and palliative measures

• Antacid therapy — the ATS/ERS/JRS/ALAT 2022 guideline makes a conditional recommendation AGAINST antacid medication and AGAINST antireflux surgery for the treatment of IPF.^[1]
• Palliative care — early integration with symptom-focused care and advance care planning.^[1]

The subtypes that change the answer — NSIP, COP, HP, and the rest

The label changes the drug, so each subtype deserves its own sentence. Steroid-responsive disease (NSIP cellular, COP) sits at the opposite pole from IPF — confusing them is the cardinal error.^[1]

Idiopathic pulmonary fibrosis (IPF)

• The clinical archetype. Older smoker, basal Velcro crackles, clubbing, restrictive defect, UIP on HRCT. Diagnosis by MDT without biopsy when the HRCT is diagnostic.
• Genetic/familial form — exam lists still name MUC5B and telomerase mutations; those names are not in the cited abstracts and are labelled exam convention.^[6]

Non-specific interstitial pneumonia (NSIP)

• Definition has evolved — NSIP was originally defined by pathology and has moved to a multidisciplinary diagnosis, understood today in the context of chronic fibrosing and progressive ILD.^[13]
• A mimic, and mimicked — subacute and chronic hypersensitivity pneumonitis can mimic NSIP (and UIP), which is why the diagnosis demands a high index of suspicion and multidisciplinary review.^[9]
• Treatment — because fibrotic NSIP overlaps with progressive fibrosing ILD, management follows the same multidisciplinary, progression-focused pathway.^[1]

Cryptogenic organising pneumonia (COP / idiopathic BOOP)

• Organising pneumonia is a non-specific lung parenchymal response to any form of injury; when no cause is found it is cryptogenic organising pneumonia (COP).^[11]
• Clinical picture — subacute or subclinical infection-like illness that does not respond to antibiotics.^[11]
• Pathology — polypoid granulation tissue (Masson bodies) in the alveolar spaces, with lung architecture preserved in most patients.^[11]
• Imaging and treatment — CT shows classic, nodular and fibrotic phenotypes, and clinical outcomes are good after steroid treatment.^[11]

Hypersensitivity pneumonitis (HP)

• A syndrome of repeated antigen exposure — HP results from repeated exposure to a variety of organic particles, presenting as acute, subacute, or chronic clinical forms that frequently overlap.^[9]
• HRCT — ground-glass and poorly defined nodules with patchy air trapping in acute/subacute disease; reticular opacities, volume loss and traction bronchiectasis in chronic disease.^[9]
• A great mimicker — subacute and chronic HP can mimic NSIP and UIP, so HP should be considered in any patient presenting with clinical evidence of interstitial lung disease.^[9]
• Diagnosis — requires exposure to a known antigen plus the assemblage of clinical, radiologic, laboratory and pathologic findings.^[9]
• Management — early diagnosis and avoidance of further exposure are the keys; corticosteroids are generally used although their long-term efficacy is unproven in prospective trials; lung transplantation for progressive end-stage illness.^[9]

Smoking-related IIPs — RB-ILD and DIP

• Respiratory bronchiolitis-associated ILD (RB-ILD) — smokers, mild symptoms, diffuse centrilobular micronodules and ground-glass, bronchial wall thickening. Treat with smoking cessation; steroids rarely needed.
• Desquamative interstitial pneumonia (DIP) — heavy smokers, diffuse ground-glass; smoking cessation plus corticosteroids; better prognosis than IPF.^[1]

Acute interstitial pneumonia (AIP / Hamman-Rich syndrome)

Etymology for viva gold: Hamman-Rich syndrome is the eponym for acute interstitial pneumonia — named for Louis Hamman and Arnold Rich, who described the fulminant fibrosing illness in 1944, decades before anyone split it from chronic IPF. It is rapidly progressive (days to weeks) respiratory failure with diffuse alveolar damage histologically — indistinguishable from ARDS. A sourced >50 percent mortality is not in the cited abstracts; treat supportively (lung-protective ventilation, oxygen, antibiotics, cautious steroids).^[1]

Lymphoid interstitial pneumonia (LIP)

A lymphocytic interstitial infiltrate; think Sjögren syndrome, HIV (paediatric), common variable immunodeficiency. It may progress to lymphoma; treat the underlying condition; corticosteroids ± rituximab.^[1]

Connective tissue disease-associated ILD (CTD-ILD)

• Systemic sclerosis — ILD is a common manifestation of systemic sclerosis and a leading cause of systemic sclerosis-related death.^[5]
• Treatment — nintedanib 150 mg twice daily slowed the annual rate of FVC decline in SENSCIS (−52.4 versus −93.3 mL per year, difference 41.0 mL, P=0.04). 576 patients received at least one dose; 48.4 percent were already on mycophenolate. The modified Rodnan skin score and SGRQ did not differ.^[5]
• Mycophenolate mofetil — SLS II compared mycophenolate 1500 mg twice daily for 24 months with oral cyclophosphamide 2.0 mg/kg per day for 12 months. The primary endpoint was negative (p=0.24); both arms improved %FVC (2.19 versus 2.88). Leucopenia occurred in 4 versus 30 patients. Prefer mycophenolate for tolerability, not greater 24-month efficacy.^[8]
• Other connective tissue diseases — management is individualised by the underlying disease under joint rheumatology–ILD team review.^[1]

Drug-induced ILD

• Drug-induced interstitial lung disease (DIILD) is an increasingly recognised complication of modern antineoplastic therapy — molecular targeted agents, immune checkpoint inhibitors and antibody-drug conjugates all carry risk, and toxicity can significantly affect clinical outcomes.^[12]
• Amiodarone, bleomycin, methotrexate and nitrofurantoin remain classical exam causes of drug-induced ILD; stop the suspected drug.^[12]
• Diagnosis — a systematic, exclusion-based approach agreed by a multidisciplinary team; vigilant monitoring and early detection are central to management.^[12]

Pneumoconioses

• Asbestosis — amphibole/crocidolite fibres; lower-lobe interstitial fibrosis, pleural plaques (the radiological hallmark of exposure), benign pleural effusion, diffuse pleural thickening, rounded atelectasis, mesothelioma, and an increased risk of lung cancer (synergistic with smoking).
• Silicosis — crystalline silica; upper-zone nodular opacities, progressive massive fibrosis, eggshell-calcified hilar lymph nodes; a greatly increased risk of TB (silico-tuberculosis). Caplan syndrome (rheumatoid pneumoconiosis) with rheumatoid nodules.
• Coal worker's pneumoconiosis — upper-zone small rounded opacities; Caplan syndrome.
• Berylliosis — non-caseating granulomas indistinguishable from sarcoidosis; the beryllium lymphocyte proliferation test (BeLPT) is diagnostic.
• Hard metal disease — cobalt/tungsten carbide exposure; giant cell interstitial pneumonitis.^[1]

Rare diffuse lung diseases

• Lymphangioleiomyomatosis (LAM) — women of reproductive age; diffuse thin-walled cysts throughout both lungs; chylous pleural effusion, pneumothorax, abdominal angiomyolipomas; sirolimus (everolimus) stabilises lung function (mTOR inhibitors).
• Pulmonary Langerhans cell histiocytosis (LCH) — smokers; upper-zone cysts and nodules, pneumothorax, pituitary and bone lesions; CD1a+, S100+, CD207/Langerin+ cells; smoking cessation is the cornerstone.
• Pulmonary alveolar proteinosis — surfactant accumulation; crazy-paving pattern; anti-GM-CSF antibodies (autoimmune); whole-lung lavage; inhaled or subcutaneous GM-CSF.
• Eosinophilic pneumonia — acute (Löffler-like) and chronic; peripheral eosinophilia; upper-lobe predominance of the chronic form ("photographic negative of pulmonary oedema"); steroid responsive.^[1]

How ILD patients come to harm

Complications separate by mechanism — and the preventable ones are the ones examiners test.^[1]

• Respiratory failure — type 1, then mixed type 2 in end-stage disease.
• Pulmonary hypertension (group 3) and cor pulmonale — an independent marker of poor prognosis.
• Acute exacerbation of IPF — triggered versus idiopathic (IWG 2016); exclude heart failure and volume overload. In-hospital 50 percent and 3–4 month post-AE survival figures are not in the Kishaba abstract and are not taught as sourced numbers here.^[10]
• Lung cancer — may coexist with IPF; a sourced 3-to-7-fold relative risk is not in the cited abstracts.
• Spontaneous pneumothorax — particularly in LAM, LCH, lymphoid interstitial pneumonia.
• Pleural disease — asbestosis (plaques, effusion, mesothelioma); rheumatoid effusion.
• Opportunistic infection — PJP, CMV, mycobacterial — particularly in immunosuppressed CTD-ILD.
• Drug toxicity — amiodarone, bleomycin, methotrexate and nitrofurantoin remain classical exam causes; modern DIILD also follows targeted agents, immune checkpoint inhibitors and antibody-drug conjugates. Amiodarone 33 percent / bleomycin 3–25 percent mortality figures are not in the Naraoka review and are not taught as sourced numbers here.^[12]
• Diagnostic pitfalls — overcalling UIP on an HRCT that lacks honeycombing (favour NSIP); missing chronic HP behind a "fibrotic ILD" label; missing a CTD behind "lung-dominant" disease; sending a frail elderly patient for VATS biopsy when the HRCT is already diagnostic.

Prognosis — the GAP index and the numbers that set it

Prognosis varies enormously across the ILDs — from excellent to rapidly fatal — and the label sets it. Reproduce the numbers that examiners quote.^[1]

• IPF has an overall poor prognosis (Ley). Exam texts still quote median survival of three to five years; that band is not in the Martinez, Raghu or Kishaba abstracts and is not taught as a sourced figure here.^[14]
• Acute exacerbation — IWG 2016 triggered versus idiopathic; exclude heart failure and volume overload. In-hospital 50 percent / 3–4 month figures dropped as sourced numbers.^[10]
• COP — good clinical outcomes after steroid treatment; antibiotics fail.^[11]
• Cellular versus fibrotic NSIP — exam grouping; NSIP is a multidisciplinary diagnosis today.^[13]
• RB-ILD / DIP — smoking-related IIPs; smoking cessation is the first move (exam grouping).
• Anti-MDA5 rapidly progressive ILD — a time-critical MDT emergency; a sourced 20–60 percent 6-month mortality is not in the cited abstracts.^[1]

The GAP index — Gender, Age, Physiology staging system

The GAP index (Ley 2012) uses four variables: gender (G), age (A), and two lung physiology variables (P) — FVC and DLCO. Three stages had 1-year mortality of 6 percent, 16 percent and 39 percent respectively.^[14]

The point-score table (0–8 mapping to stages I–III) and the 3-year 16 / 48 / 62 percent bands that circulate in exams are not in the Ley abstract and are labelled exam convention, not sourced figures.^[14]

The ILD-GAP and Composite Physiologic Index (CPI) are later extensions; they are not in the 2012 abstract cited here.^[14]

Disposition

• Every patient with new, suspected, or progressive ILD is managed under a specialist ILD service / MDT.
• Antifibrotics are initiated and monitored by the ILD team.
• Transplant referral happens early.
• Palliative care is integrated as fibrosis progresses.^[1]

Special populations — pregnancy, elderly, immunocompromised

Presentation, thresholds, and drug safety all shift in these groups — examiners love them.^[1]

• Paediatric ILD (chILD syndrome) — a very different differential: neuroendocrine cell hyperplasia of infancy (NEHI), pulmonary interstitial glycogenosis (PIG), surfactant dysfunction disorders (SP-B, SP-C, ABCA3 mutations), developmental disorders. Requires a specialist paediatric ILD centre.
• Pregnancy — most ILDs tolerate pregnancy if function is preserved; pirfenidone and nintedanib are NOT recommended (insufficient teratogenicity data; nintedanib has embryo-foetal toxicity in animals); plan pregnancy with the ILD team.
• Elderly — frailty and comorbidity dominate; an HRCT-first strategy avoids biopsy; antifibrotics are started earlier; transplant is rarely an option beyond 70.
• Immunocompromised / transplant / HIV — a broad differential (opportunistic infection, drug pneumonitis, GVHD, organising pneumonia); BAL is critical.
• Anticoagulated patients — balance bleeding risk against biopsy; an HRCT-first diagnostic pathway.
• Occupational medicolegal — asbestosis, silicosis, berylliosis are compensable; document exposure meticulously; engage occupational health.^[1]

The guidelines and trials that changed practice

Name the guideline, name the trial, name what each changed — that is the viva.^[1]

• ATS/ERS/JRS/ALAT 2022 Clinical Practice Guideline (Raghu 2022) — updates prior IPF guidelines and addresses progression of pulmonary fibrosis in ILDs other than IPF. Radiological and histopathological criteria for IPF were updated by consensus. Conditional recommendation: transbronchial lung cryobiopsy is an acceptable alternative to surgical lung biopsy in experienced centres. Conditional recommendations against antacid medication and against antireflux surgery for treating IPF. PPF = at least two of three criteria (worsening symptoms, radiological progression, physiological progression) within the past year in an ILD other than IPF. Conditional nintedanib for PPF; more research on pirfenidone.^[1]
• INPULSIS (Richeldi 2014, NEJM) — nintedanib slowed FVC decline: −114.7 mL per year with nintedanib versus −239.9 mL with placebo (INPULSIS-1) and −113.6 versus −207.3 mL per year (INPULSIS-2).^[2]
• ASCEND (King 2014, NEJM) — pirfenidone produced a 47.9 percent relative reduction in the proportion of patients with an absolute decline of 10 percentage points or more in predicted FVC or death, and improved progression-free survival.^[3]
• INBUILD (Flaherty 2019, NEJM) — nintedanib 150 mg twice daily reduced FVC decline by 107.0 mL per year in progressive fibrosing ILDs other than IPF. Eligibility used progression in the past 24 months — that is not the ATS 2022 PPF definition (past year).^[4][1]
• SENSCIS (Distler 2019, NEJM) — nintedanib slowed FVC decline in SSc-ILD (−52.4 versus −93.3 mL per year; difference 41.0 mL per year).^[5]
• SLS II (Tashkin 2016, Lancet Respir Med) — mycophenolate 1500 mg twice daily for 24 months versus oral cyclophosphamide 2.0 mg/kg per day for 12 months. Primary endpoint negative (p=0.24); both improved %FVC (2.19 versus 2.88); leucopenia 4 versus 30. Prefer mycophenolate for tolerability, not greater efficacy.^[8]
• PANTHER-IPF (NEJM 2012) — prednisone plus azathioprine plus N-acetylcysteine increased death and hospitalisation; combination immunosuppression was abandoned.^[7]

The mnemonics that earn marks

The high-yield recall list — carry these into the viva:^[1]

• UIP pattern on HRCT — predominantly bilateral, peripheral, basal reticular changes with traction bronchiectasis and clusters of subpleural cystic airspaces (honeycombing).^[6]
• Diagnosis — exclude other ILDs and overlapping conditions; identify UIP usually on HRCT, with lung biopsy reserved for some patients.^[6]
• Two antifibrotics available — pirfenidone (2403 mg per day in ASCEND) and nintedanib (150 mg twice daily in INPULSIS) decrease physiological progression.^[6][3][2]
• IPF reflects aberrant repair — repetitive alveolar epithelial injury in a genetically susceptible ageing individual, not primary inflammation.^[6]
• PANTHER-IPF — prednisone plus azathioprine plus NAC increases death and hospitalisation; do NOT use combination immunosuppression in IPF.^[7]
• HP — a syndrome of repeated exposure to organic particles; subacute and chronic HP mimic NSIP and UIP; management rests on early diagnosis and avoidance of further exposure.^[9]
• COP — organising pneumonia is a non-specific response to injury; outcomes are good after steroid treatment.^[11]
• Drug-induced ILD — molecular targeted agents, immune checkpoint inhibitors and antibody-drug conjugates all cause it; diagnose by exclusion with an MDT.^[12]
• SSc-ILD — ILD is a common manifestation of systemic sclerosis and a leading cause of SSc-related death; nintedanib slows FVC decline (SENSCIS). SLS II: mycophenolate and cyclophosphamide both improved %FVC; prefer mycophenolate for tolerability, not greater 24-month efficacy.^[5][8]

Ward-round test — three stems, thirty seconds each

The mantra

Listen for Velcro at the bases, HRCT for the pattern, exclude every cause — and an antifibrotic, not a steroid, for IPF.^[1]