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Restrictive & Interstitial Lung Disease

Name: Restrictive & Interstitial Lung Disease
Creator: Veli Bakalov, MD

Stiff lungs, dusty jobs, and noncaseating granulomas

Respiratory·Interstitial & Pulmonary Vascular Disease·5 min read·9 high-yield points·Reviewed by Veli Bakalov, MD @HemeOncBuddy

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Restriction = ↓ TLC with a normal or increased FEV1/FVC (often ≥0.8), because FEV1 falls proportionally less than FVC.
Normal DLCO and A-a gradient = extrapulmonary restriction (obesity, scoliosis, myasthenia gravis, Guillain-Barré, ALS); low DLCO and a widened A-a gradient = interstitial disease.
Upper lobes: coal, silica, beryllium; lower lobes: asbestosis, with ferruginous bodies and calcified parietal pleural plaques that mark exposure but are not premalignant.
Silicosis (sandblasting, mining, foundry): eggshell calcification of hilar nodes; silica disrupts macrophage phagolysosomes → ↑ TB risk.
Asbestos causes bronchogenic carcinoma more often than mesothelioma (smoking multiplies the lung cancer risk), yet it is the classic cause of mesothelioma, which is not smoking-related.
Caplan syndrome = pneumoconiosis + rheumatoid arthritis with lung nodules; berylliosis (aerospace, electronics) mimics sarcoid with noncaseating granulomas and responds to steroids.
IPF: older man with dry cough, clubbing, and Velcro crackles; UIP pattern (patchy subpleural basal fibrosis, honeycombing, fibroblastic foci); treat with pirfenidone or nintedanib.
Sarcoidosis: noncaseating granulomas, bilateral hilar adenopathy, ↑ ACE, high BAL CD4/CD8 ratio, and hypercalcemia from macrophage 1α-hydroxylase (↑ calcitriol); Löfgren syndrome has a good prognosis.
Hypersensitivity pneumonitis (farmer's lung, bird-fancier's lung, hot-tub lung) is a type III/IV reaction; acute disease reverses with antigen avoidance, chronic exposure causes fibrosis.

The restrictive pattern

Small, stiff lungs. Restrictive disease limits how far the lungs can expand. TLC (the defining measurement), FVC, and FEV1 all fall, but FEV1 falls proportionally less, so FEV1/FVC is normal or increased (often ≥0.8). In fibrotic lungs, extra elastic recoil pulls the airways open and speeds expiration, which is why the ratio can rise.

Where is the restriction? DLCO and the A-a gradient localize it. Extrapulmonary restriction (chest wall or neuromuscular) leaves the alveolar-capillary membrane intact, so DLCO and the A-a gradient are normal; any hypoxemia comes from hypoventilation, with a rising PaCO₂. Interstitial (parenchymal) disease thickens and destroys that membrane, so DLCO is LOW and the A-a gradient widens.

Two kinds of restriction

Feature	Extrapulmonary	Interstitial (parenchymal)
Examples	Obesity, scoliosis (chest wall); myasthenia gravis, Guillain-Barré, ALS (neuromuscular)	Pneumoconioses, IPF, sarcoidosis, hypersensitivity pneumonitis, drugs (e.g., bleomycin, amiodarone, methotrexate)
Problem	Weak respiratory muscles or a rigid, loaded chest wall	Fibrotic, noncompliant lung tissue
DLCO	Normal	↓
A-a gradient	Normal	↑

Pneumoconioses: occupational dusts

Common mechanism. Inhaled mineral particles are engulfed by alveolar macrophages, which release inflammatory and fibrogenic mediators; after years of exposure, nodular or diffuse fibrosis produces restrictive physiology. Lobe distribution is a key clue: coal, silica, and beryllium favor the upper lobes, while asbestosis favors the lower lobes.

Coal worker's pneumoconiosis. Coal mining dust fills macrophages with carbon, forming upper-lobe nodules that can coalesce into progressive massive fibrosis. Caplan syndrome is pneumoconiosis plus rheumatoid arthritis with lung (rheumatoid) nodules. Anthracosis, the asymptomatic carbon pigment of city dwellers and smokers, is benign.

Silicosis. Sandblasting, mining, and foundry work produce upper-lobe silicotic nodules of whorled collagen and "eggshell" calcification of hilar lymph nodes. Silica disrupts macrophage phagolysosomes, impairing killing of Mycobacterium tuberculosis, so silicosis raises TB risk (silicotuberculosis); it also raises lung cancer risk.

Asbestosis. Shipyard, insulation, roofing, and plumbing exposure causes LOWER-lobe interstitial fibrosis. Biopsy shows ferruginous bodies: golden-brown, beaded asbestos fibers coated with iron and protein (Prussian blue positive). Ivory-white calcified pleural plaques on the parietal pleura and diaphragm mark exposure, not severity, and are not premalignant.

Asbestos and cancer. The most common asbestos-related malignancy is bronchogenic carcinoma, and smoking multiplies that risk. Asbestos is nevertheless the classic cause of malignant mesothelioma, which arises from pleura after a long latency, presents with pleural effusion and thickening, and is NOT smoking-related.

Berylliosis. Beryllium exposure in aerospace, electronics, and ceramics triggers a cell-mediated reaction with noncaseating granulomas indistinguishable from sarcoidosis, predominantly in the upper lobes. Lung cancer risk rises; the granulomatous disease responds to corticosteroids.

Pneumoconioses

Disease	Exposure	Lobes	Hallmarks	Complications
Coal worker's	Coal mining	Upper	Carbon-laden macrophages, nodules	Progressive massive fibrosis; Caplan syndrome
Silicosis	Sandblasting, mining, foundry	Upper	Silicotic nodules; eggshell hilar node calcification	Tuberculosis, lung cancer
Asbestosis	Shipyards, insulation, roofing, plumbing	Lower	Ferruginous bodies; calcified pleural plaques	Bronchogenic carcinoma > mesothelioma
Berylliosis	Aerospace, electronics, ceramics	Upper	Noncaseating granulomas (sarcoid-like)	Lung cancer; steroid-responsive

Asbestos is the only one of these dusts that targets the lower lobes.

Idiopathic pulmonary fibrosis

Pathogenesis. Repeated injury to the alveolar epithelium, followed by aberrant repair, drives fibroblast activation (TGF-β is central) and progressive interstitial fibrosis. Aging and smoking are risk factors; the classic patient is an older man.

Usual interstitial pneumonia (UIP) pattern. Patchy, heterogeneous fibrosis that is subpleural and basal-predominant, with honeycombing (cystic spaces lined by bronchiolar epithelium) and fibroblastic foci of active fibrosis beside older scar.

Clinical picture. Insidious dyspnea, dry cough, clubbing, and fine "Velcro" crackles at the bases; PFTs are restrictive with a low DLCO. IPF is a diagnosis of exclusion: rule out hypersensitivity pneumonitis, connective tissue disease, drugs, and pneumoconioses.

Treatment. Antifibrotics slow the loss of lung function: pirfenidone (dampens TGF-β–driven fibroblast proliferation) or nintedanib (tyrosine kinase inhibitor of PDGF, FGF, and VEGF receptors). Steroids do not help, and lung transplant is the definitive option.

Sarcoidosis

Noncaseating granulomas. Sarcoidosis is a systemic, CD4⁺ Th1-driven granulomatous disease of unknown cause. The classic patient is a young African-American woman with bilateral hilar lymphadenopathy, with or without reticular lung opacities. Granulomas are noncaseating and may contain asteroid bodies (star-shaped inclusions in giant cells) and Schaumann bodies (laminated calcium-protein concretions); BAL shows a high CD4/CD8 ratio. Diagnosis requires biopsy and exclusion of TB, fungi, and berylliosis.

Labs. Serum ACE is elevated (made by granuloma epithelioid cells) and ESR is often high. Hypercalcemia and hypercalciuria occur because granuloma macrophages express 1α-hydroxylase and make calcitriol independent of PTH, which is suppressed.

Granuloma macrophagesExpress 1α-hydroxylase
Activate vitamin D25-OH D → 1,25-(OH)₂ D
Gut Ca²⁺ absorption upHypercalcemia, hypercalciuria

Sarcoid hypercalcemia

A great mimic. Beyond restrictive lung disease, sarcoid causes uveitis, erythema nodosum, lupus pernio (violaceous facial plaques), arrhythmia and heart block, and facial (Bell) palsy. Löfgren syndrome (erythema nodosum + bilateral hilar adenopathy + arthralgia) carries a good prognosis. Most cases resolve spontaneously; corticosteroids are reserved for severe or progressive disease.

Hypersensitivity pneumonitis

Immune reaction to inhaled organic antigen. A mixed type III (immune complex) and type IV (T cell) reaction in the alveoli and small airways, unlike the IgE-driven bronchial reaction of asthma. Classic exposures: farmer's lung (thermophilic actinomycetes in moldy hay), bird-fancier's lung (avian proteins in droppings and feathers), and hot-tub lung (aerosolized mycobacteria).

Course. Acute episodes bring fever, cough, and dyspnea hours after exposure; histology shows interstitial inflammation with poorly formed noncaseating granulomas. Acute disease reverses with antigen avoidance, whereas chronic exposure leads to irreversible fibrosis.

Noncaseating granulomas in the lung: sarcoidosis (no exposure), berylliosis (metal exposure), or hypersensitivity pneumonitis (organic antigen, poorly formed granulomas). The history separates them.