Interstitial Lung Disease

Interstitial lung disease (ILD) is an umbrella term for a heterogeneous group of >200 diffuse parenchymal lung diseases (DPLDs) that primarily injure the alveolar interstitium, producing inflammation and/or fibrosis. For NEET PG, the high-yield triad is idiopathic pulmonary fibrosis (IPF), hypersensitivity pneumonitis (HP) and sarcoidosis — tied together by a restrictive PFT pattern, characteristic HRCT signatures, and disease-specific bronchoalveolar lavage (BAL) findings.

Definition and classification

ILDs share the final common pathway of alveolar-capillary unit damage, leading to a thickened interstitium, impaired gas exchange and a restrictive ventilatory defect. The modern ATS/ERS classification divides DPLDs into four broad buckets:

Category	Examples	Key clue
Known cause	Drugs (amiodarone, methotrexate, bleomycin, nitrofurantoin), connective tissue disease (RA, SSc, dermatomyositis), pneumoconioses (asbestosis, silicosis)	History/exposure
Idiopathic interstitial pneumonias (IIPs)	IPF, NSIP, COP, AIP, DIP, RB-ILD, LIP	HRCT pattern
Granulomatous	Sarcoidosis, hypersensitivity pneumonitis	Granulomas on biopsy
Other/rare	LAM, Langerhans cell histiocytosis, eosinophilic pneumonia, pulmonary alveolar proteinosis	Distinct radiology

High-yield: The single most common idiopathic interstitial pneumonia is IPF, and the histological/radiological pattern that defines it is usual interstitial pneumonia (UIP).

A useful first split is upper-zone vs lower-zone predominant disease:

• Upper-zone (mnemonic "CHARTS"): Coal worker's pneumoconiosis, Histiocytosis/Hypersensitivity pneumonitis (chronic), Ankylosing spondylitis, Radiation, Tuberculosis/silicosis, Sarcoidosis.
• Lower-zone (mnemonic "RASIO"): Rheumatoid arthritis, Asbestosis, Scleroderma, IPF (idiopathic pulmonary fibrosis), Other CTD/drugs.

Etiology and pathophysiology

Idiopathic pulmonary fibrosis (IPF)

The prevailing model is not chronic inflammation but repetitive alveolar epithelial micro-injury in a genetically susceptible, ageing lung. Injured type II pneumocytes drive aberrant wound healing — TGF-β release, fibroblast-to-myofibroblast transformation, and fibroblastic foci that deposit excess collagen. This explains why anti-inflammatory immunosuppression fails in IPF and why antifibrotics are the mainstay. Risk factors: age >60, male, smoking, gastro-oesophageal reflux, and genetic variants (MUC5B promoter polymorphism — strongest common risk allele; telomerase TERT/TERC and surfactant SFTPC mutations in familial disease).

Hypersensitivity pneumonitis (HP / extrinsic allergic alveolitis)

An immunologically mediated reaction to inhaled organic antigens. Acute/subacute forms are type III (immune-complex); chronic forms involve type IV (T-cell, granulomatous) hypersensitivity. Classic antigen–disease pairs:

Disease	Antigen / source
Farmer's lung	Thermophilic actinomycetes (mouldy hay)
Bird fancier's / pigeon breeder's lung	Avian proteins (droppings, feathers)
Bagassosis	Mouldy sugarcane (Thermoactinomyces sacchari)
Mushroom worker's lung	Compost actinomycetes
Hot tub lung	Mycobacterium avium complex
Maple bark stripper's	Cryptostroma

Sarcoidosis

A multisystem non-caseating granulomatous disease of unknown cause, with a hypothesised T-helper-1 (Th1)/exaggerated cellular immune response to an unidentified antigen. Granulomas can include Schaumann bodies (calcified) and asteroid bodies (stellate inclusions). Hypercalcaemia/hypercalciuria arises because activated macrophages express 1-α-hydroxylase, converting 25-OH-vitamin D to active 1,25-(OH)₂ vitamin D (calcitriol). Epidemiology favours young adults (20–40 y), females, and is notably more common and severe in African ancestry. The granulomas are typically "naked" (sparse surrounding lymphocytes) and arrange in a perilymphatic distribution, which underlies the radiological and bronchoscopic findings. Spontaneous remission is common, reflecting that sarcoid is fundamentally an immune-mediated, often self-limiting, process rather than a relentless fibrotic one (except advanced stage IV).

Clinical features

Common to most ILDs: progressive exertional dyspnoea, a dry (non-productive) cough, fatigue, and on examination fine bibasal end-inspiratory "Velcro" crackles plus digital clubbing (especially IPF). Cor pulmonale and pulmonary hypertension mark advanced disease.

Disease-specific pearls:

• IPF: insidious dyspnoea over months–years in an elderly smoker; clubbing in ~50%; rapid deterioration = acute exacerbation.
• HP: acute form mimics a flu-like illness 4–8 h after heavy exposure (fever, chills, cough, dyspnoea) that improves on weekends/holidays away from the antigen — a classic exam temporal clue. Chronic HP → fibrosis and clubbing.
• Sarcoidosis: often asymptomatic with incidental BHL on CXR. Löfgren syndrome = erythema nodosum + bilateral hilar lymphadenopathy (BHL) + arthralgia + fever — carries an excellent prognosis and is often self-limiting. Extrapulmonary: uveitis, lupus pernio (violaceous nose/cheek plaques — pathognomonic skin sign), facial nerve palsy (Heerfordt syndrome = uveoparotid fever + parotid enlargement + facial palsy + fever), hypercalcaemia, cardiac (arrhythmia, heart block).

High-yield: A young/middle-aged patient with erythema nodosum, painful ankles and BHL on chest X-ray = Löfgren syndrome — biopsy often unnecessary; manage conservatively/NSAIDs.

Diagnosis and investigation of choice

The pivotal investigation across ILDs is high-resolution CT (HRCT) of the thorax. Confirm physiology with PFTs and add disease-specific tests.

Pulmonary function tests (PFTs)

ILD produces a restrictive pattern:

Parameter	ILD finding
FEV₁	↓
FVC	↓
FEV₁/FVC ratio	Normal or ↑ (>0.7, often >0.8)
TLC, RV, FRC	↓ (reduced lung volumes)
DLCO	↓ (earliest and most sensitive)
KCO	variable

High-yield: A reduced DLCO with a preserved/raised FEV₁/FVC ratio and low lung volumes is the signature of restrictive ILD — contrast with obstructive COPD where FEV₁/FVC < 0.7.

HRCT patterns — the exam workhorse

UIP pattern (IPF): subpleural, basal-predominant reticulation, traction bronchiectasis, and the defining feature — honeycombing (clustered subpleural cystic airspaces). Distribution is heterogeneous (patchy) with minimal ground-glass.

NSIP pattern: bilateral, symmetric, basal ground-glass opacities with subpleural sparing; homogeneous; honeycombing is scarce. NSIP is the typical pattern in connective-tissue-disease ILD (e.g., scleroderma) and carries a better prognosis than UIP.

HP (chronic): upper/mid-zone, centrilobular ground-glass nodules, mosaic attenuation and air-trapping ("three-density / headcheese sign" on expiratory imaging).

Sarcoidosis: perilymphatic micronodules along bronchovascular bundles and fissures, with bilateral hilar + right paratracheal lymphadenopathy — the classic "1-2-3 sign" (right paratracheal + bilateral hilar) and "lambda" pattern on gallium scan. Egg-shell nodal calcification can mimic silicosis.

High-yield: Honeycombing is the radiological hallmark of established fibrosis (UIP) and predicts a poor prognosis. Ground-glass opacity generally implies active, potentially reversible inflammation (e.g., NSIP, acute HP) — distinguishing reversible from irreversible disease is a recurring single-best-answer theme.

Stepwise diagnostic flow

Suspect ILD (dyspnoea + Velcro crackles) → CXR (screen) → HRCT thorax (define pattern) → PFT + DLCO (confirm restriction & severity) → serology (ANA, RF, anti-CCP, anti-Scl-70, myositis panel to exclude CTD) → multidisciplinary discussion (MDD) → BAL ± surgical/transbronchial lung biopsy if pattern is indeterminate.

High-yield: If HRCT shows a definite UIP pattern in the right clinical setting, a lung biopsy is NOT required to diagnose IPF — MDD confirms it. Biopsy is reserved for indeterminate/atypical patterns.

BAL — differentiating the types

Disease	Dominant BAL cell	Note
Sarcoidosis	Lymphocytes, CD4:CD8 ratio > 3.5 (high)	Ratio >3.5 highly specific
Hypersensitivity pneumonitis	Lymphocytes, CD4:CD8 LOW (CD8 predominant)	Marked lymphocytosis (often >50%)
IPF / UIP	Neutrophils ± eosinophils	Non-specific
Asbestosis	Neutrophils + ferruginous (asbestos) bodies
Pulmonary alveolar proteinosis	Milky, PAS-positive lipoproteinaceous fluid	"Crazy-paving" HRCT
Langerhans cell histiocytosis	CD1a+ cells, Birbeck granules

Sarcoidosis-specific tests

• Serum ACE is raised in ~60% but is neither sensitive nor specific — used for monitoring activity, not diagnosis.
• Histology: non-caseating granuloma is the gold standard; obtained via endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) of mediastinal nodes — the modern investigation of choice.
• Kveim–Siltzbach test (intradermal injection of sarcoid spleen tissue): historically positive but obsolete due to infection-transmission risk — still examined as an eponym.
• Diagnosis of exclusion: must rule out TB and lymphoma first — caseation on biopsy points away from sarcoid and towards TB.
• Other markers: raised serum/urinary calcium, hypergammaglobulinaemia, and cutaneous anergy (negative tuberculin test despite Th1 activity) classically accompany sarcoidosis.
• Workup for organ involvement: ECG and echocardiography (cardiac sarcoid), slit-lamp exam (uveitis), serum calcium, LFTs, and baseline PFTs with DLCO. FDG-PET / gallium-67 can map disease activity in equivocal cases.

High-yield: Sarcoidosis = high CD4:CD8 (>3.5); HP = low CD4:CD8 (CD8 high) — a perennially asked one-liner.

Management and drug of choice

IPF

Antifibrotics slow FVC decline (they do not reverse fibrosis):

• Pirfenidone — antifibrotic/anti-TGF-β; adverse effects: photosensitivity rash, GI upset, deranged LFTs.
• Nintedanib — intracellular tyrosine kinase inhibitor (VEGFR/FGFR/PDGFR); adverse effect: diarrhoea, raised LFTs.
• Supportive: smoking cessation, long-term oxygen if hypoxic, pulmonary rehabilitation, vaccination, treat GORD, manage pulmonary hypertension.
• Definitive: lung transplantation — the only curative option; IPF is a leading transplant indication.
• Steroids/immunosuppression are contraindicated in stable IPF; the PANTHER-IPF trial showed the prednisolone + azathioprine + N-acetylcysteine triple therapy increased mortality.

High-yield: Drug of choice in IPF = pirfenidone or nintedanib (antifibrotics). Triple immunosuppression is harmful — a frequently tested negative-marking trap.

Hypersensitivity pneumonitis

• Antigen avoidance is the cornerstone and most important step.
• Corticosteroids for acute severe or progressive subacute disease; antifibrotics (nintedanib) for the fibrotic chronic phenotype.

Sarcoidosis

• Many cases (especially Löfgren / asymptomatic stage I) resolve spontaneously — observe.
• Oral corticosteroids are first-line when treatment is indicated: progressive pulmonary disease, hypercalcaemia, cardiac, neurological, or ocular involvement.
• Second-line/steroid-sparing: methotrexate, azathioprine; infliximab for refractory/neurosarcoidosis.

Sarcoid CXR stage	Findings	Spontaneous remission
0	Normal	—
I	BHL only	~60–80%
II	BHL + parenchymal infiltrates	~50%
III	Parenchymal infiltrates only (no BHL)	~30%
IV	Fibrosis (irreversible)	rare

Complications

• Respiratory failure (type 1 hypoxaemic) and acute exacerbation of IPF (sudden worsening, new ground-glass on UIP background — high mortality).
• Pulmonary hypertension and cor pulmonale.
• Lung cancer — IPF and asbestosis both raise bronchogenic carcinoma risk; asbestos also causes mesothelioma (independent of fibrosis).
• Sarcoidosis: hypercalcaemia → nephrocalcinosis/renal stones; cardiac sarcoid (sudden death, heart block); blindness from chronic uveitis; neurosarcoidosis.
• Pneumothorax in cystic ILDs (LAM, Langerhans cell histiocytosis).
• Treatment toxicity (steroid effects, nintedanib hepatotoxicity).

Key differentials

• Congestive cardiac failure / pulmonary oedema — bibasal crackles + dyspnoea; differentiate with BNP, echo and HRCT (no honeycombing).
• COPD — obstructive (FEV₁/FVC < 0.7), hyperinflation; can coexist as CPFE (combined pulmonary fibrosis and emphysema) with paradoxically preserved lung volumes but very low DLCO.
• Lymphangitic carcinomatosis — nodular interlobular septal thickening, often unilateral, known primary.
• Pneumocystis / atypical pneumonia — ground-glass, immunocompromise.
• Connective-tissue-disease ILD — always screen serology; NSIP pattern, younger patients, extrapulmonary features.
• Pneumoconioses vs HP vs sarcoid — distinguished by exposure history, zone predominance and BAL CD4:CD8 ratio.

Recently asked / exam angle

• HRCT honeycombing + subpleural basal reticulation = UIP/IPF — single most repeated image-based stem.
• BAL CD4:CD8 ratio: high (>3.5) → sarcoid; low → HP — direct one-liner MCQ.
• PANTHER-IPF: immunosuppression increases mortality → antifibrotics (pirfenidone/nintedanib) are correct; "steroids" is the distractor.
• Mechanism of action: nintedanib = tyrosine kinase inhibitor; pirfenidone = anti-TGF-β/antifibrotic (assertion-reason format).
• Löfgren syndrome triad and its good prognosis.
• Hypercalcaemia in sarcoid due to macrophage 1-α-hydroxylase → calcitriol.
• Antigen pairs (bagassosis–sugarcane, bird fancier's–avian protein, farmer's lung–thermophilic actinomycetes).
• Drug-induced ILD: amiodarone, methotrexate, bleomycin, nitrofurantoin — "which drug causes pulmonary fibrosis" recall.
• DLCO is the earliest/most sensitive PFT abnormality and the best monitor of progression.
• Most common IIP = IPF; best-prognosis IIP pattern = NSIP/COP.

Rapid revision

1. ILD = restrictive PFT: ↓ FVC, ↓ TLC, normal/↑ FEV₁/FVC, ↓ DLCO (DLCO earliest to fall).
2. IPF = UIP pattern = subpleural + basal honeycombing + traction bronchiectasis on HRCT.
3. IPF is antifibrotic-treated (pirfenidone, nintedanib); immunosuppression is harmful (PANTHER-IPF).
4. Nintedanib = tyrosine kinase inhibitor; pirfenidone causes photosensitivity.
5. MUC5B promoter variant = strongest genetic risk for IPF.
6. Sarcoidosis: non-caseating granuloma, BHL, CD4:CD8 > 3.5 in BAL, raised serum ACE, hypercalcaemia via macrophage 1-α-hydroxylase.
7. HP: low CD4:CD8 (CD8 high), upper-zone, antigen-related; treat by antigen avoidance ± steroids.
8. Löfgren syndrome = erythema nodosum + BHL + arthralgia → excellent prognosis.
9. Lupus pernio = pathognomonic cutaneous sarcoid; Heerfordt = uveoparotid fever.
10. NSIP = symmetric basal ground-glass with subpleural sparing; commonest pattern in CTD-ILD, better prognosis than UIP.
11. Asbestosis = lower-zone fibrosis + pleural plaques + ferruginous bodies; raises lung cancer and mesothelioma risk.
12. Definitive cure for end-stage IPF = lung transplantation; Kveim test is an obsolete eponym for sarcoid.