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 on HRCT or surgical lung biopsy and no identifiable cause. Median survival from diagnosis is three to five years — worse than many common cancers, and the number that should sharpen your referral.[1]

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 classification that examiners quote is the ATS/ERS 2013 Travis multidisciplinary framework (updated 2022). It reorganises the idiopathic interstitial pneumonias by clinical–radiological–pathological pattern rather than histology alone — and the diagnosis is made by an ILD multidisciplinary team (MDT), which may legitimately change its mind as new data arrive. A label is never one person's call.[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:[1]

• Prevalence of IPF is 14 to 43 per 100 000 population; annual incidence 7 to 11 per 100 000 in North America and Europe.[1]
• Age — IPF is a disease of older adults; mean age at diagnosis 65 to 70 years, rare under 50.
• Sex — men affected roughly 2:1 over women.
• Smoking — current or former smokers carry a 2 to 3-fold increased risk of IPF; smoking is also the principal driver of RB-ILD, DIP, and pulmonary Langerhans cell histiocytosis.
• Occupational — metal and wood dust, farming, hairdressing, and stone cutting are over-represented in ILD registries.
• Genetics — familial pulmonary fibrosis (autosomal dominant, incomplete penetrance) accounts for 3 to 20 percent of cases. Key genes: MUC5B promoter polymorphism (rs35705950) — the strongest common risk allele; telomerase complex mutations (TERT, TERT promoter, TERC, RTEL1, PARN); surfactant protein mutations (SFTPC, SFTPA2, ABCA3). Short telomere length predicts worse prognosis and informs family screening.

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. The old "inflammation precedes fibrosis" model was discarded for one reason: anti-inflammatory therapy failed to alter the disease course. Remember that single fact and the entire drug strategy makes sense.[1]

The wound-healing cascade runs in five linked steps:[1]

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 the honeycomb lung: cystic spaces lined by bronchiolar epithelium, embedded in dense fibrous tissue.[1]

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. Pulmonary vascular pruning and secondary vascular remodelling produce group 3 pulmonary hypertension in roughly a third of advanced cases.[1]

Acute exacerbation of IPF is the catastrophic clinical event — diffuse alveolar damage (the histological pattern of ARDS) superimposed on underlying UIP, with rapid gas-exchange failure and an in-hospital mortality near 50 percent. The other IIPs run different programmes: NSIP is more uniform and temporally homogeneous; COP is granulation-tissue polyps occluding distal airways (a defect of resolution of injury, not perpetuation); HP is a type III plus type IV hypersensitivity reaction to inhaled antigen with poorly formed granulomas.[1]

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 — present in roughly half of IPF patients; when present, it predicts a worse prognosis.
• 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. A fall in SpO₂ of 4 percent or more to a value below 88 percent is a significant desaturation and an independent predictor of mortality in IPF.[5]

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: TLC below 80 percent predicted (or below the lower limit of normal), FVC reduced, FEV1 reduced proportionally, FEV1/FVC preserved or increased (often greater than 0.8). 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 (1 to 3 mm collimation, prone plus supine, inspiratory plus expiratory). The four UIP criteria (ATS/ERS/JRS/ALAT 2018/2022):[1]
  1. Basal and subpleural predominance
  2. Reticular abnormality (intralobular and interlobular septal thickening)
  3. Honeycombing (clustered cystic airspaces, typically 3 to 10 mm, with well-defined walls)
  4. Traction bronchiectasis and bronchiolectasis
  • Plus the absence of features inconsistent with UIP (listed below).
• Features inconsistent with UIP — upper-zone or peribronchovascular predominance; extensive ground-glass exceeding reticulation; profuse micronodules; multiple cysts away from areas of honeycombing; diffuse mosaic attenuation or air trapping; consolidation.
• HRCT diagnostic levels (2018/2022 ATS/ERS/JRS/ALAT):
  • UIP — all four criteria met (no biopsy needed)
  • Probable UIP — clearly basal subpleural reticulation and traction bronchiectasis but definitive honeycombing absent
  • Indeterminate for UIP — features of fibrosis but the pattern does not fit UIP
  • Alternative diagnosis — features suggesting a non-UIP entity (e.g. extensive ground-glass, nodules)
• Varicose bronchiectasis within areas of fibrosis is highly characteristic of UIP.

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 — lymphocytic alveolitis (lymphocytes 30 to 70 percent), CD4/CD8 ratio reduced (often below 1).
• Sarcoidosis — lymphocytic alveolitis with CD4/CD8 ratio above 3.5.
• Diffuse alveolar damage / acute exacerbation — bloody, neutrophilic, hyaline membrane fragments.
• Diffuse alveolar haemorrhage — increasingly bloody return, hemosiderin-laden macrophages exceeding 20 percent.
• Eosinophilic pneumonia — eosinophils above 25 percent.
• Infection — PJP stain/PCR, AFB, fungal stains, viral PCR.[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 — larger samples, rising evidence, lower morbidity than surgical biopsy.
• Surgical lung biopsy (VATS) — the gold-standard tissue sample when HRCT is indeterminate and the MDT considers a non-IPF diagnosis plausible. Multiple lobes biopsied. Contraindicated in advanced disease, severe hypoxaemia, or significant comorbidity.[1]

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 (mean PAP 25 mmHg or above at rest with PCWP 15 mmHg or below equals pre-capillary, WHO group 3).
• 24-hour oesophageal pH / impedance — strong association between IPF and gastro-oesophageal reflux; reflux is a putative driver of micro-aspiration.
• 6-minute walk test — functional and prognostic (desaturation).
• Lung cancer screening — IPF carries a 3 to 7-fold increased risk of lung cancer; consider low-dose CT in eligible smokers.[1]

When ILD decompensates — the acute bundle

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 — titrate to maintain SpO₂ at 88 to 92 percent (target PaO₂ at or above 60 mmHg / 8 kPa). High-flow nasal cannula may bridge selected patients to transplant.
2. Acute exacerbation of IPF (AE-IPF) — defined by idiopathic acute worsening of dyspnoea within 30 days, with new bilateral ground-glass or consolidation on HRCT not fully explained by cardiac failure or fluid overload. Management is largely supportive:
   • Empiric broad-spectrum antibiotics pending cultures (e.g. piperacillin-tazobactam 4.5 g IV every 8 hours ± macrolide).
   • High-dose corticosteroid — methylprednisolone 0.5 to 1 g IV daily for three days, then tapered (evidence low quality; common practice).
   • Treat precipitating factors — infection, aspiration, drug toxicity, surgery.
   • Mechanical ventilation in advanced IPF is generally unhelpful (in-hospital mortality above 80 percent); consider only as a bridge to transplant in transplant-eligible patients.
3. Pulmonary hypertensive crisis — supplementary oxygen, cautious diuresis (furosemide 20 to 40 mg IV), a pulmonary vasodilator (sildenafil 20 mg orally every 8 hours), and ICU support.
4. Massive haemoptysis (rare in ILD; occurs in LAM, diffuse alveolar haemorrhage) — airway protection, lateral decubitus affected side down, urgent bronchial artery embolisation.[1]

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 antifibrotics are licensed; both slow the rate of FVC decline by approximately 100 mL per year — neither reverses fibrosis. That "slow, not cure" framing is the line that earns viva marks.[1]

The INPULSIS trial showed nintedanib reduced the annual rate of FVC decline from 239 mL/year (placebo) to 113 mL/year in IPF.[2] The ASCEND trial showed pirfenidone reduced FVC decline and improved progression-free survival.[3] The INBUILD trial extended nintedanib's benefit to progressive fibrosing ILDs beyond IPF — fibrotic NSIP, HP, CTD-ILD, asbestos-related fibrosis.[4]

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

Everyone forgets: corticosteroids and immunosuppressants do NOT work in IPF. The inflammation model was discarded after they failed to alter the course — and combining them actively harms.[1]

• Azathioprine plus prednisolone plus N-acetylcysteine (NAC) combination — the PANTHER-IPF trial (2012) was stopped early for increased mortality, hospitalisation and adverse events; combination immunosuppression is contraindicated in IPF.
• Anticoagulation (warfarin) — no benefit; bleeding risk.
• Corticosteroid monotherapy — no benefit in IPF; may cause harm.
• Stem cell therapy, imatinib, endothelin antagonists (bosentan, macitentan), TNF-α inhibitors — no demonstrated benefit; possible harm.[1]

The preventable harm: missing the UIP pattern and giving immunosuppression that hastens decline — or, worse, triggers an acute exacerbation. Read the HRCT before you reach for the prednisolone.[1]

4. Long-term oxygen therapy (LTOT)

Prescribe if PaO₂ at or below 55 mmHg (7.3 kPa) at rest (room air, stable state), SpO₂ at or below 88 percent, or PaO₂ at or below 60 mmHg with evidence of pulmonary hypertension, cor pulmonale, or secondary polycythaemia. Use at least 15 hours per day including sleep.[1]

5. Pulmonary rehabilitation

A structured 6 to 8 week exercise, education and breathlessness-management programme improves 6MWT distance, dyspnoea score, and quality of life in ILD (evidence extrapolated from COPD and corroborated by ILD-specific trials).[1]

6. Lung transplantation — the only cure

Refer early to a transplant centre — ideally within three months of IPF diagnosis — because waiting-list mortality in IPF is the highest of any transplant indication. Bilateral sequential lung transplant is preferred in IPF. The lung allocation score (LAS) is weighted towards severity and wait-list urgency, favouring IPF. Five-year post-transplant survival is approximately 50 to 60 percent. Upper age limits (commonly 65 to 70 years) and frailty constrain eligibility.[1]

7. Pulmonary hypertension therapy

Group 3 PH — manage the underlying lung disease aggressively first. Pulmonary vasodilators (sildenafil, bosentan, riociguat, macitentan) may be considered in severe PH, ideally within a specialist PH-MDT. Trials in IPF-PH have been largely disappointing (RISE-IIP, INSTAGE).[1]

8. Supportive and palliative measures

• Antacid therapy — NICE recommends this for IPF with confirmed reflux; consider laparoscopic anti-reflux surgery in selected patients.
• Cough suppression — thalidomide (limited), low-dose morphine for refractory cough in the palliative setting; speech and language therapy techniques.
• Vaccinations — annual influenza, pneumococcal (PCV13 plus PPSV23), COVID-19, RSV (older adults), herpes zoster.
• Palliative care — early integration; low-dose opioids (oral morphine 2.5 mg every 4 to 6 hours) for refractory dyspnoea; oxygen even with normal SpO₂ if symptomatically helpful; 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 — MUC5B rs35705950, telomerase (TERT/TERC) mutations. Screen first-degree relatives if onset is under 50 or there is a strong family history.[1]

Non-specific interstitial pneumonia (NSIP)

• Common in CTD (especially systemic sclerosis), occasionally idiopathic.
• Cellular subtype — inflammation, ground-glass, responds well to corticosteroids (prednisolone 0.5 to 1 mg/kg/day tapered) ± immunosuppression (mycophenolate, azathioprine).
• Fibrotic subtype — poorer prognosis, behaves like IPF; consider antifibrotics.
• HRCT — symmetric basal ground-glass, fine reticulation, sparing of the immediate subpleural stripe at the bases, traction bronchiectasis, no honeycombing.[1]

Cryptogenic organising pneumonia (COP / idiopathic BOOP)

• Subacute flu-like illness with dry cough, dyspnoea, fever, weight loss.
• HRCT — patchy, often peripheral or peribronchovascular consolidation and ground-glass, sometimes nodules, migratory on serial imaging.
• Dramatic response to corticosteroids — prednisolone 0.75 to 1 mg/kg/day, taper over 6 to 12 months; relapse is common on taper. Macrolides, cyclophosphamide, rituximab in resistant cases.
• Secondary organising pneumonia — infection, drugs (amiodarone, methotrexate, checkpoint inhibitors), radiation, CTD, post-transplant; treat the cause.[1]

Hypersensitivity pneumonitis (HP)

• Acute HP — 4 to 12 hours after heavy antigen exposure; fever, chills, cough, dyspnoea; resolves in hours to days away from antigen.
• Subacute/chronic HP — insidious cough, exertional dyspnoea, weight loss, basal crackles.
• Classic antigens — bird fancier's (pigeon, budgerigar, droppings and bloom), farmer's lung (mouldy hay, Saccharopolyspora rectivirgula, Thermoactinomyces vulgaris), humidifier lung, hot-tub lung (Mycobacterium avium complex), mushroom worker, malt worker (Aspergillus clavatus).
• HRCT — mid/upper-zone, centrilobular ground-glass nodules, mosaic attenuation, air trapping on expiratory images; the chronic stage shows upper-zone fibrosis.
• BAL — lymphocytosis with CD4/CD8 below 1.
• Management — antigen avoidance (essential and most effective); corticosteroids (prednisolone 0.5 mg/kg/day, taper) for subacute/chronic or severe acute; mycophenolate or azathioprine as steroid-sparing.[1]

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. Mortality is above 50 percent; 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 — NSIP is most common; screen with HRCT and PFTs at diagnosis and annually; early mycophenolate mofetil 2 to 3 g/day or tocilizumab for progressive disease; nintedanib for progressive SSc-ILD (SENSCIS trial).
• Rheumatoid arthritis — often UIP pattern, with a worse prognosis than IPF; treat with mycophenolate or rituximab (avoid methotrexate if methotrexate lung is suspected).
• Polymyositis/dermatomyositis / antisynthetase syndrome — anti-Jo-1, anti-PL-7, anti-PL-12, anti-EJ, anti-OJ; anti-MDA5 portends rapidly progressive ILD. Combination immunosuppression (high-dose steroids, tacrolimus/cyclophosphamide, rituximab, IVIG).
• Sjögren, SLE, MCTD — variable patterns; treat the CTD.[1]

Drug-induced ILD

• Amiodarone — phospholipidosis; chronic interstitial pneumonitis, organising pneumonia, rarely ARDS; HRCT may show high attenuation. Risk is dose-related (above 400 mg/day, longer than 2 years). Stop the drug, give corticosteroids.
• Bleomycin — dose-related (above 450 units cumulative); oxygen augments toxicity (use the lowest FiO₂); pneumonitis can progress to fibrosis; treat with steroids.
• Methotrexate — granulomatous pneumonitis; eosinophilia; stop, give steroids.
• Nitrofurantoin — acute or chronic pneumonitis; the chronic form can mimic IPF.
• Checkpoint inhibitors (nivolumab, pembrolizumab, ipilimumab) — immune-related pneumonitis at any time; hold the drug, give grade-based steroids (1 to 2 mg/kg/day prednisolone), infliximab for refractory disease.[1]

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]

Radiation-induced lung disease

• Acute radiation pneumonitis (within 6 to 12 weeks) — dry cough, dyspnoea, geographic ground-glass confined to the radiation field; treat with prednisolone 1 mg/kg/day tapering over weeks.
• Chronic radiation fibrosis (6 to 12 months) — traction bronchiectasis and volume loss in the field; usually irreversible.[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 — in-hospital mortality around 50 percent; median survival post-AE approximately three to four months.[1]
• Lung cancer — IPF carries a 3 to 7-fold increased risk; consider screening.
• 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 pulmonary toxicity mortality up to 33 percent; bleomycin lung 3 to 25 percent mortality.
• 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 median survival 3 to 5 years from diagnosis; some patients survive over 10 years.
• Acute exacerbation in-hospital mortality around 50 percent; median post-AE survival 3 to 4 months.
• AIP mortality above 50 percent within weeks.
• COP — steroid-responsive, excellent prognosis; relapses on taper are common.
• Cellular NSIP — good prognosis; fibrotic NSIP behaves like IPF.
• RB-ILD / DIP — a slow course with smoking cessation.
• Antisynthetase with anti-MDA5 — rapidly progressive ILD, 6-month mortality 20 to 60 percent if untreated.[1]

The GAP index — Gender, Age, Physiology staging system

The GAP index (Ley 2012) is a simple validated four-variable mortality predictor for IPF, reproduced verbatim.[5]

Total 0 to 8 maps to Stages I (0 to 3), II (4 to 5), III (6 to 8). Stage I: 1-year mortality 6 percent, 3-year 16 percent; Stage II: 1-year 17 percent, 3-year 48 percent; Stage III: 1-year 39 percent, 3-year 62 percent.[1]

The ILD-GAP extends the score to other ILDs (additional variables: underlying diagnosis, presence of pulmonary hypertension). The Composite Physiologic Index (CPI) uses FVC, FEV1 and DLCO and predicts mortality across fibrotic ILD.[1]

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) — the current standard; a conditional recommendation for pirfenidone and nintedanib; a conditional recommendation against anticoagulation, immunosuppression, and stem cell therapy in IPF.[1]
• NICE CG163 (2013) Idiopathic Pulmonary Fibrosis in Adults — the UK service specification: specialist ILD MDT, early access to antifibrotics, oxygen, pulmonary rehab, and palliative care.
• NICE TA379 Pirfenidone for IPF — restricted to FVC between 50 percent and 80 percent predicted; treatment stopped if disease progresses by 10 percent FVC in any 12-month period.
• INPULSIS (Richeldi 2014, NEJM) — nintedanib reduced FVC decline from 239 to 113 mL/year in IPF.[2]
• ASCEND (King 2014, NEJM) — pirfenidone reduced FVC decline by 132 mL at 52 weeks and improved progression-free survival.[3]
• INBUILD (Flaherty 2019, NEJM) — nintedanib reduced FVC decline by 107 mL/year across progressive fibrosing ILDs other than IPF.[4]
• PANTHER-IPF (NEJM 2012, 2014) — azathioprine plus prednisone plus NAC increased mortality and hospitalisation; combination immunosuppression was abandoned.
• SENSCIS — nintedanib slowed FVC decline in SSc-ILD.
• BTS / BTS-ILD registry — UK epidemiology and outcomes.

The mnemonics that earn marks

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

• Restrictive pattern — low TLC, low FVC, low DLCO, normal or raised FEV1/FVC (the mirror image of obstructive).
• IPF is the commonest IIP and has the worst prognosis — median survival 3 to 5 years.
• Velcro crackles — fine, late-inspiratory, basal, non-clearing; the bedside signature of UIP.
• HRCT UIP — basal, subpleural, honeycombing plus traction bronchiectasis, little ground-glass; diagnostic without biopsy when all four criteria are met.
• Two antifibrotics — pirfenidone (titrate to 600 mg TID; LFT monitoring) and nintedanib (150 mg BID; diarrhoea, LFTs). Both slow decline by about 100 mL FVC/year; neither reverses fibrosis.
• PANTHER-IPF — azathioprine plus prednisolone plus NAC harms; do NOT use combination immunosuppression in IPF.
• 6MWT desaturation — an independent predictor of mortality.
• Lung transplant is the only cure — refer early; bilateral sequential; the LAS favours IPF.
• COP/BOOP — the steroid-responsive ILD with patchy migratory consolidation.
• NSIP — symmetric basal ground-glass ± reticulation; the cellular subtype responds to steroids; it spares the extreme subpleural base.
• Hypersensitivity pneumonitis — upper-zone, mosaic attenuation, centrilobular nodules; CD8+ BAL lymphocytosis.
• Asbestosis — lower-lobe fibrosis plus pleural plaques; risk of mesothelioma and lung cancer.
• Silicosis — upper-zone, eggshell calcification of hilar nodes; high TB risk.
• Berylliosis — non-caseating granulomas; mimics sarcoid; the BeLPT is diagnostic.
• Amiodarone lung — phospholipidosis; high-attenuation lung on HRCT; mortality up to 33 percent.
• LAM — cystic, women, chylous effusion; sirolimus.
• LCH — smokers, upper-zone cysts plus nodules; smoking cessation.
• Alveolar proteinosis — crazy-paving, anti-GM-CSF; whole-lung lavage.
• Telomerase (TERT/TERC) mutations — familial pulmonary fibrosis; worse prognosis.
• GAP index equals Gender, Age, FVC, DLCO — Stages I to III predict mortality.[1]

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]