8.3 Interstitial Lung Disease & Sarcoidosis

Interstitial lung diseases (ILDs) encompass a diverse group of over 200 non-neoplastic conditions affecting the alveolar epithelium, pulmonary capillary endothelium, and surrounding perialveolar mesenchymal tissue. For MRCP(UK) Part 1, candidates must master the diagnostic features of Idiopathic Pulmonary Fibrosis (IPF), distinguishing features of secondary connective tissue and drug-induced ILDs, the immunological and bronchoalveolar profile of hypersensitivity pneumonitis, and the multifaceted clinical, biochemical, and radiological spectrum of sarcoidosis.

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1. Idiopathic Pulmonary Fibrosis (IPF)

IPF is a specific, chronic, progressive fibrosing interstitial pneumonia of unknown cause, occurring primarily in older adults and limited strictly to the lungs. It is associated with the histopathological and radiological pattern of Usual Interstitial Pneumonia (UIP).

Pathogenesis & Epidemiology

• Demographics: Male predominance (approx. 2:1), typical age $> 60\text{ years}$; strong association with active or prior cigarette smoking (relative risk ~1.6), environmental dust exposures (metal, wood, silica), chronic microaspiration secondary to gastro-oesophageal reflux disease (GERD), and genetic variants (e.g., $MUC5B$ promoter polymorphism, telomerase reverse transcriptase [$TERT/TERC$] mutations).
• Mechanism: Repetitive subclinical microinjury to alveolar epithelial type II cells leads to aberrant epithelial-mesenchymal crosstalk. Instead of normal physiological re-epithelialization, exuberant production of pro-fibrotic mediators (transforming growth factor-beta [TGF-$\beta$], platelet-derived growth factor [PDGF], fibroblast growth factor [FGF]) drives persistent myofibroblast proliferation and excessive extracellular matrix deposition. Progressive parenchymal architectural distortion causes lung honeycombing, loss of capillary gas exchange units, and refractory hypoxaemia.

Clinical Presentation & Examination

• Symptoms: Insidious onset of progressive exertional breathlessness and an intractable, dry, non-productive hacking cough lasting months to years.
• Signs:
  • Bilateral fine, bibasal, end-inspiratory 'Velcro' crackles: Auscultated predominantly at the posterior lung bases; characteristically persist after coughing (unlike secretions in bronchitis).
  • Digital clubbing: Present in $50\text{–}70%$ of patients.
  • Late signs: Central cyanosis, loud pulmonary second sound ($P_2$), peripheral oedema, and right ventricular heave reflecting secondary pulmonary hypertension and cor pulmonale.

High-Resolution Computed Tomography (HRCT): The UIP Pattern

Thin-slice ($1\text{ mm}$) volumetric HRCT of the chest is the central diagnostic imaging modality. In an appropriate clinical context, a Definite UIP pattern on HRCT precludes the necessity of an invasive surgical lung biopsy.

• Hallmark Features of UIP:
  1. Subpleural and basal predominance: Fibrosis is concentrated along the periphery of the lower lung zones.
  2. Reticular opacities: Interlobular and intralobular septal thickening.
  3. Traction bronchiectasis and bronchiolectasis: Irregular bronchial dilation caused by fibrous parenchymal retractile forces.
  4. Honeycombing: Clustered, thick-walled, cystic airspaces ($3\text{–}10\text{ mm}$) arranged in multiple layers beneath the pleura.
  5. Absence of inconsistent/atypical features: No extensive ground-glass opacities exceeding reticulation, no profuse micronodules, no mosaic perfusion or air trapping, and no peribronchovascular predominance.

Pulmonary Function Tests (PFTs)

• Restrictive Ventilatory Defect: Reduced Forced Vital Capacity ($\text{FVC} < 80%$ predicted) and Total Lung Capacity ($\text{TLC} < 80%$ predicted).
• Preserved/Elevated Ratio: $\text{FEV}_1/\text{FVC} \ge 0.75\text{–}0.85$ (proportional reduction in both parameters, or higher due to increased radial parenchymal tethering).
• Transfer Factor: Disproportionate, profound reduction in the transfer factor for carbon monoxide ($\text{TLCO}$) and transfer coefficient ($\text{KCO}$), indicating alveolar-capillary barrier destruction.
• Desaturation: Significant drop in $\text{SpO}_2$ during the 6-minute walk test (6MWT).

Evidence-Based Antifibrotic Pharmacotherapy

• Landmark clinical trials (ASCEND and INPULSIS) established that antifibrotic agents halve the annual rate of FVC decline (~$100\text{ mL/year}$ reduction in loss), decreasing disease progression and acute exacerbations, though they do not reverse established fibrotic scarring.
• NICE Eligibility Criteria: Initiated only in confirmed IPF when baseline $\text{FVC}$ is between $50%$ and $80%$ predicted.
  • Pirfenidone: Oral pyridone with antifibrotic and anti-inflammatory mechanisms; inhibits TGF-$\beta$ synthesis and collagen production. Adverse effects: Marked cutaneous photosensitivity, rash, nausea, dyspepsia, and elevated liver enzymes.
  • Nintedanib: Oral intracellular tyrosine kinase inhibitor blocking vascular endothelial growth factor receptor (VEGFR), platelet-derived growth factor receptor (PDGFR), and fibroblast growth factor receptor (FGFR). Adverse effects: Severe diarrhoea ($> 60%$ of patients), abdominal cramping, and hepatotoxicity.
• Contraindicated Regimens: Immunosuppressive therapy with high-dose corticosteroids, azathioprine, and N-acetylcysteine was evaluated in the landmark PANTHER-IPF trial; it was terminated early due to significantly increased mortality and hospitalization rates. Immunosuppression must never be used in IPF.

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2. Secondary Interstitial Lung Diseases & Hypersensitivity Pneumonitis

Connective Tissue Disease-Associated ILD (CTD-ILD)

• Systemic Sclerosis (SSc): ILD complicates up to $80%$ of systemic sclerosis (predominantly diffuse cutaneous SSc with anti-topoisomerase I / anti-Scl-70 antibodies). The characteristic HRCT pattern is Non-Specific Interstitial Pneumonia (NSIP), defined by symmetrical, bibasal ground-glass opacities with fine reticulation, traction bronchiectasis, and characteristic subpleural sparing (absence of peripheral honeycombing).
• Rheumatoid Arthritis (RA-ILD): Affects older men with active erosive disease, high-titre Rheumatoid Factor, and anti-cyclic citrullinated peptide (anti-CCP). Uniquely among CTDs, RA-ILD most commonly produces a UIP pattern (honeycombing) indistinguishable from IPF.
• Antisynthetase Syndrome: Autoimmune myopathy characterized by antibodies directed against aminoacyl-tRNA synthetases (most commonly anti-Jo-1 [histidyl-tRNA synthetase]). The clinical pentad includes:
  1. Rapidly progressive, aggressive interstitial lung disease (NSIP or organizing pneumonia pattern).
  2. Inflammatory myositis (proximal muscle weakness, elevated creatine kinase).
  3. "Mechanic's hands": Hyperkeratotic, fissured, cracked, hyperpigmented scaling along the radial margins of the fingers.
  4. Symmetrical non-erosive inflammatory polyarthritis.
  5. Raynaud's phenomenon and unexplained fevers.

Drug-Induced Interstitial Lung Diseases

• Amiodarone: Accumulates within alveolar macrophages, producing characteristic foamy, vacuolated macrophages with lamellar inclusion bodies on cytology. Presents with subacute cough, breathlessness, and high-attenuation consolidation or ground-glass infiltrates on CT due to high iodine content. Discontinuation and corticosteroid therapy are required.
• Bleomycin: Induces direct DNA strand breakage and reactive oxygen species generation, causing acute pulmonary toxicity in up to $10%$. Risk multiplies with cumulative dose ($> 400,000\text{ units}$), impaired renal excretion, and exposure to high fractional inspired oxygen concentrations ($\text{FiO}_2$) during general anaesthesia.
• Methotrexate: Causes acute/subacute hypersensitivity pneumonitis (fever, dry cough, peripheral eosinophilia in $50%$, diffuse ground-glass opacities); typically responds rapidly to drug cessation and corticosteroids.
• Nitrofurantoin: Acute presentation resembles an acute allergic reaction (fever, dyspnoea, peripheral eosinophilia, bilateral infiltrates, pleural effusions within hours to days); chronic presentation produces insidious bibasal fibrosis resembling IPF following months of urinary tract prophylaxis.

Hypersensitivity Pneumonitis (Extrinsic Allergic Alveolitis)

An immunologically mediated inflammatory reaction affecting the terminal bronchioles and alveolar interstitium following repeated inhalation of organic aeroantigens or chemical haptens in sensitized individuals. Combines Type III (immune complex / Arthus reaction) and Type IV (cell-mediated delayed-type) hypersensitivity.

• HRCT Hallmark Features: Mid-to-upper lung zone predilection; poorly defined centrilobular ground-glass micronodules; mosaic attenuation; and expiratory lobular air trapping. The co-existence of normal parenchyma, ground-glass opacity, and air trapping produces the pathognomonic "three-density pattern" (formerly "headcheese sign").
• Bronchoalveolar Lavage (BAL): Demonstrates marked lymphocytosis ($> 40\text{–}50%$ lymphocytes) with a decreased or inverted CD4:CD8 ratio ($< 1.0$), sharply differentiating it from sarcoidosis.
• Management: Strict, absolute avoidance of the inciting antigen is curative in acute/subacute disease. Systemic corticosteroids (oral prednisolone) hasten resolution of acute inflammatory infiltrates.

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3. Sarcoidosis: Multisystem Granulomatous Disease

Sarcoidosis is a multisystem, systemic inflammatory disease of unknown aetiology characterized by the formation of non-caseating epithelioid-cell granulomas in affected organs, most prominently the lungs, intrathoracic lymph nodes, eyes, and skin. It arises from an exaggerated cell-mediated Th1 immune response driven by interleukin-2 (IL-2), interferon-gamma (IFN-$\gamma$), and tumour necrosis factor-alpha (TNF-$\alpha$).

Clinical Syndromes & Extrapulmonary Manifestations

• Löfgren's Syndrome: A classic acute, self-limiting clinical presentation characterized by the triad of:
  1. Erythema nodosum: Painful, violaceous, tender subcutaneous nodules along the extensor surfaces of the lower legs.
  2. Bilateral hilar lymphadenopathy (BHL): Symmetrical, well-demarcated hilar and paratracheal node enlargement on chest radiography.
  3. Migratory polyarthritis / periarthritis: Predominantly involving the ankles and knees, accompanied by fever.
  • Prognosis: Outstanding; $> 80\text{–}90%$ experience spontaneous complete resolution within 1 to 2 years without long-term sequelae. First-line management comprises non-steroidal anti-inflammatory drugs (NSAIDs); corticosteroids are rarely required.
• Heerfordt's Syndrome (Uveoparotid Fever): Characterized by uveitis (anterior or posterior), parotid gland enlargement, facial nerve palsy (lower motor neuron Bell's palsy), and low-grade pyrexia.
• Organ-Specific Involvement:
  • Cutaneous: Lupus pernio (violaceous indurated plaques across the nose, cheeks, and earlobes; strongly correlates with chronic, refractory pulmonary disease and poor prognosis), maculopapular sarcoid, subcutaneous nodules.
  • Ocular: Anterior uveitis, chronic granulomatous panuveitis, retinal vasculitis, conjunctival nodules (mandates routine slit-lamp examination).
  • Neurological (Neurosarcoidosis): Cranial nerve palsies (cranial nerve VII most frequent), lymphocytic aseptic meningitis, hypothalamic-pituitary dysfunction (diabetes insipidus, hyperprolactinaemia), peripheral neuropathy.
  • Cardiac: Myocardial granulomatous infiltration causing ventricular tachyarrhythmias, complete heart block, sudden cardiac death, and dilated cardiomyopathy.

Scadding Chest Radiographic Staging

Calcium Metabolism & Biochemical Markers

• Hypercalcaemia (approx. $10%$) & Hypercalciuria (approx. $30%$):
  • Epithelioid macrophages within non-caseating sarcoid granulomas independently and autonomously express $1\alpha$-hydroxylase (CYP27B1).
  • This enzyme converts inactive circulating 25-hydroxyvitamin D into active 1,25-dihydroxyvitamin D (calcitriol) independent of parathyroid hormone (PTH).
  • Elevated calcitriol promotes hyperabsorption of calcium in the small intestine and stimulates osteoclastic bone resorption.
  • Laboratory profile: Elevated corrected serum calcium, suppressed serum PTH ($< 1.0\text{ pmol/L}$), elevated 1,25-(OH)$_2$-vitamin D, and hypercalciuria (predisposing to nephrocalcinosis, nephrolithiasis, and chronic renal failure).
• Serum Angiotensin-Converting Enzyme (ACE): Secreted by granuloma epithelioid cells; elevated in ~60% of patients with active sarcoidosis. Lacks diagnostic specificity (elevated in TB, silicosis, Gaucher's disease, hyperthyroidism) but serves as an adjunctive marker to track disease activity.
• Bronchoalveolar Lavage (BAL): Reveals marked CD4+ T-cell lymphocytosis with a characteristically elevated CD4:CD8 ratio ($> 3.5$), opposite to hypersensitivity pneumonitis.

Indications for Systemic Corticosteroid Therapy

Asymptomatic Stage I or stable Stage II sarcoidosis does not require immunosuppression. Definite indications for systemic corticosteroids (oral prednisolone $20\text{–}40\text{ mg}$ daily, followed by slow titration) include:

1. Symptomatic or severe hypercalcaemia / hypercalciuria with impaired renal function.
2. Cardiac sarcoidosis (conduction blocks, arrhythmias, cardiomyopathy).
3. Neurosarcoidosis (cranial palsies, meningitis, optic neuritis).
4. Active ocular disease refractory to topical therapy.
5. Disfiguring cutaneous lesions (lupus pernio).
6. Progressive, disabling pulmonary symptoms accompanied by deteriorating lung function (drop in FVC $> 10%$ or TLCO $> 15%$) or worsening Stage II/III parenchymal infiltrates.

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4. Comprehensive Comparison of Interstitial Lung Diseases