Interstitial lung disease

Interstitial Lung Disease
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Overview
Classification Fibrosis lung response Occupational lung disease Drug-induced lung injury Radiation-induced lung injury Smoking related interstitial lung disease Idiopathic interstitial pneumonia Pulmonary alveolar proteinosis Lymphocytic infiltrative disorders Pulmonary lymphangioleiomyomatosis Pulmonary hemorrhage syndromes Interstitial lung disease associated with systemic diseases Granulomatous lung response
Pathophysiology
Differentiating Interstitial Lung Disease from other Diseases
Laboratory Finidngs

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Sadaf Sharfaei M.D.[2], Anmol Pitliya, M.B.B.S. M.D.[3], Saarah T. Alkhairy, M.D.

Synonyms and keywords: Diffuse parenchymal lung disease; DPLD; ILD

Overview

Interstitial lung disease is a group of disorders involving pulmonary parenchyma. The exact pathogenesis of these disorders is not completely understood. There are multiple initiating factors that may lead to pulmonary injury. However, immunopathogenic responses of lung tissue are quite similar. The major histopathologic patterns in response to lung injury include inflammation, fibrosis and granulomatous response. Interstitial lung disease may be classified into several subtypes based on the lung response to tissue injury and the cause of injury. The underlying cause of interstitial lung disease may include factors such as toxic environmental or occupational exposure, cigarette smoking, and radiation. Interstitial lung disease may also be idiopathic.

Classification

Interstitial lung disease may be classified on the basis of lung response to tissue injury. The lung response to tissue injury may be characterized as:

• Granulomatous
• Alveolitis, interstitial inflammation, and fibrosis

Interstitial lung disease

Lung Response: Granulomatous

Lung Response: Alveolitis, Interstitial Inflammation, and Fibrosis

Known

Idiopathic (Unknown)

Hypersensitivity pneumonitis (organic dusts)

Inorganic dusts

Sarcoidosis

Lymphomatoid granulomatosis

Granulomatous vasculitides

Bronchocentric granulomatosis

Beryllium

Silica

Eosinophilic granulomatosis with polyangiitis (Churg Strauss syndrome)

Granulomatosis with polyangiitis (Wegener's)

Known cause

Idiopathic (Unknown)

Drug-induced pulmonary toxicity

Occupational and environmental exposure

Radiation-induced lung injury

Aspiration pneumonia

Smoking-related

Residual of acute respiratory distress syndrome

Inhaled inorganic dust

Inhaled organic dusts

Inhaled agents other than inorganic or organic dusts

Desquamative interstitial pneumonia

Respiratory bronchiolitis–associated interstitial lung disease

Pulmonary Langerhans cell granulomatosis

Pulmonary alveolar proteinosis

Idiopathic interstitial pneumonias

Lymphocytic infiltrative disorders (lymphocytic interstitial pneumonitis associated with connective tissue disease)

Connective tissue diseases

Gastrointestinal or liver diseases

Inherited diseases

Graft-versus-host disease

Pulmonary hemorrhage syndromes

Eosinophilic pneumonias

Lymphangioleiomyomatosis

Amyloidosis

Major idiopathic interstitial pneumonias

Rare idiopathic interstitial pneumonias

Unclassifiable idiopathic interstitial pneumonias

• Idiopathic pulmonary fibrosis • Idiopathic nonspecific interstitial pneumonia • Respiratory bronchiolitis-interstitial lung disease • Desquamative interstitial pneumonia • Cryptogenic organising pneumonia • Acute interstitial pneumonia

• Idiopathic lymphoid interstitial pneumonia • Idiopathic pleuroparenchymal fibroelastosis

• Systemic lupus erythematosus • Rheumatoid arthritis • Ankylosing spondylitis • Systemic sclerosis • Sjögren syndrome • Polymyositis • Dermatomyositis

• Crohn disease • Primary biliary cirrhosis • Chronic active hepatitis • Ulcerative colitis

• Tuberous sclerosis • Neurofibromatosis • Niemann-Pick disease • Gaucher disease • Hermansky-Pudlak syndrome

• Bone marrow transplantation • Solid organ transplantation

• Goodpasture syndrome • Idiopathic pulmonary hemosiderosis • Isolated pulmonary capillaritis

Pathophysiology

• Interstitial lung disease is a group of disorders affecting pulmonary parenchyma.
• The exact pathogenesis of these disorders is not completely understood.
• There are multiple initiating factors that may cause pulmonary injury. However, immunopathogenic responses of lung tissue are quite similar.
• There are two major histopathologic patterns in response to lung injury which include:
  • Inflammation and fibrosis pattern
  • Granulomatous pattern

Algorithm showing pathophysiology of Interstitial Lung Disease

Tissue injury in lungs

Parenchymal injury

Vascular injury

Mast cells in lungs in response to tissue injury

LPA6, LPA2, and LPA4 receptors

Decreased sFRP-1 (secreted frizzled-related protein 1) in fibroblasts

Secretes tryptase

Transforming growth factor-β (TGF-β)

Insulin-like growth factor (IGF) signalling

Reduced expression of angiogenic factors, vascular endothelial growth factor (VEGF)

Elevation of angiostatic factors, pigment epithelium-derived factor

Wnt/β-catenin signalling pathway

PAR-2/protein kinase (PK)C-α/Raf-1/p44/42 signaling pathway

Upregulation of Egr-1 (early growth response protein 1)

IGF-binding protein 5 (IGFBP-5)

IGF-binding protein 3 (IGFBP-3)

Loss of endothelial barrier function

Dysregulation of repair in lung tissue and activation of fibroblasts

Regulates transforming growth factor-β (TGF-β)

Induction of syndecan-2 (SDC2)

Activation,proliferation, and migration of fibroblast to the site of injury

Fibroblasts

Altered PTEN (phosphatase and tensin homologue)/Akt axis

Acquire contractile stress fibres

Inactivates Fox (forkhead box) O3a

Protomyofibroblast, composed of cytoplasmic actins

Pleural mesothelial cells (PMCs)

Downregulation of caveolin-1 (cav-1) and Fas expression

De novo expression of α-smooth muscle actin (α-SMA)

TGF-β1-dependent mesothelial–mesenchymal transition

Fibroblast resistant to apoptosis

Myofibroblasts

Different ranges of contractions mediated by RhoA/Rho-associated kinase

Changes in intracellular calcium concentrations

Recruitement of fibrocytes in lungs

Lock step mechanism of cyclic and contractile events

T-helper cell type 2 on site of injury

Upregulation of C-X-C chemokine receptor type 4 (CXCR4) on fibrocytes and its ligand CXCL12 (stromal cell-derived factor 1)

Excess extracellular matrix production

Exerting traction force

Interleukin-13

Migration of fibrocytes to the site of injury

Tissue remodelling

Alternate pathway activation of macrophages

Lung Fibrosis

Differentiating Interstitial Lung Disease from other Diseases

To review the complete differential diagnosis of dyspnea, click here.

To review the complete differential diagnosis of hemoptysis, click here.

To review the complete differential diagnosis of restrictive lung disease, click here.

Abbreviations: ABG: Arterial blood gas, BAL: Bronchoalveolar lavage, ESR: Erythrocyte sedimentation rate, CRP: C–reactive protein, FVC: Forced vital capacity, RV: Residual volume, FEV1: Forced expiratory volume during the 1st second, DLCO: Diffusing capacity of the lungs for carbon monoxide, O2: Oxygen, TLC: Total lung capacity, PaO2: Arterial partial pressure of oxygen, FiO2: Fraction of inspired oxygen, LDH: Lactate dehydrogenase, CEA: Carcinoembryonic antigen, Anti-GBM antibody: Anti-glomerular basement membrane antibody, A−a gradient: Alveolar-arterial gradient, PAS: Periodic acid-Schiff stain, LAM: Lymphangiomyomatosis, IgE: Immunoglobulin E, ANCA: Anti-neutrophil cytoplasmic antibody, RBC: Red blood cell, ACE: Angiotensin-converting enzyme

Disease		Clinical manifestation															Investigations
		History							Symptoms				Physical examination				Lab findings	Imaging	Pulmonary function test		Bronchoscopy and BAL	Gold standard
		Duration	Age	Gender	Family history	Smoking history	Environmental exposure	HIV	Dyspnea	Cough	Wheezing	Chest pain	Tachypnea	Auscultation	Cyanosis	Clubbing			Spirometry	ABG
Idiopathic pulmonary fibrosis		Chronic	60−70 years old	Men	+	+	±	−	+	Dry	+	+	+	Inspiratory high−pitched rhonchi Bibasilar inspiratory crackles	−	+	Antinuclear antibody + Rheumatoid factor + Elevated ESR Elevated CRP Polycythemia	Bibasilar, peripheral reticular abnormalities Focal honeycomb cyst formation Traction bronchiectasis	↓ FVC ↑ RV Normal FEV1/FVC ↓ DLCO	↓ O2	Not required ↑ Neutrophils  ↑ Eosinophils	Diagnosis of exclusion  Lung biopsy
Idiopathic nonspecific interstitial pneumonia		Acute/Chronic	50−60 years old	Female	+	−	−	+	+	+	+	−	+	Bibasilar crackles	−	±	Normal	Bilateral ground−glass opacities  Fine reticular infiltrates Traction bronchiectasis Consolidation	Normal to ↑ FEV1/FVC ↓ FVC  ↓ TLC	↓ O2	Nonspecific	Lung biopsy and multidisciplinary approach
Cryptogenic organizing pneumonia		Acute/subacute	50−60 years old	Both	−	±	−	−	+	Dry	−	−	−	Inspiratory crackles	−	−	Leukocytosis Elevated ESR Elevated CRP	Alveolar filling and air bronchograms Bilateral ground−glass opacities  Bilateral consolidation	↓ FVC Normal FEV1/FVC ↓ DLCO	↓ O2	↑ Lymphocytes ↑ Neutrophils  ↑ Eosinophils	Lung biopsy
Disease		History							Symptoms				Physical examination				Lab findings	Imaging	Pulmonary function test		Bronchoscopy and BAL	Gold standard
		Duration	Age	Gender	Family history	Smoking history	Environmental exposure	HIV	Dyspnea	Cough	Wheezing	Chest pain	Tachypnea	Auscultation	Cyanosis	Clubbing			Spirometry	ABG
Acute interstitial pneumonia (Hamman−Rich syndrome)		Acute	50−60 years old	Both	−	−	−	−	+	+	−	−	+	Diffuse crackles	−	−	Leukocytosis	Bilateral and symmetric, diffuse ground glass Alveolar consolidation opacities Traction bronchiectasis Honeycomb fibrosis	N/A	↓ O2 PaO2/FiO2 <200 mmHg	Nonspecific ↑ Neutrophils  ↑ Atypical epithelial cells	Lung biopsy
Lymphocytic interstitial pneumonia		Subacute	30−40 years old	Female	−	−	−	±	+	+	+	+	−	Diffuse crackles	−	+	Gammopathy	Diffuse ground glass attenuation with fibrosis Centrilobular and subpleural nodules Lung cysts	↓ FVC ↓ TLC ↓ DLCO	↓ O2	Nonspecific ↑ Total BAL cell count BAL lymphocytosis	Lung biopsy
Respiratory bronchiolitis−interstitial lung disease		Subacute	30−40 years old	Both	−	+	−	−	+	Dry	+	−	−	Inspiratory high−pitched rhonchi Fine, bibasilar end−inspiratory crackles	−	−	Nonspecific	Diffuse or patchy ground glass opacities in a mosaic pattern  Fine nodules  Air trapping	↓ FVC ↓ TLC ↓ DLCO	↓ O2	↑ Macrophages	Clinical evaluation and investigations
Desquamative interstitial pneumonia		Chronic	40−50 years old	Both	−	+	−	−	+	Dry	+	−	−	Fine, bibasilar end−inspiratory crackles	−	−	Nonspecific	Ground glass opacities without the peripheral reticular and reticulonodular opacities	↓ DLCO	↓ O2	↑ Eosinophils	Lung biopsy
Disease		History							Symptoms				Physical examination				Lab findings	Imaging	Pulmonary function test		Bronchoscopy and BAL	Gold standard
		Duration	Age	Gender	Family history	Smoking history	Environmental exposure	HIV	Dyspnea	Cough	Wheezing	Chest pain	Tachypnea	Auscultation	Cyanosis	Clubbing			Spirometry	ABG
Pulmonary Langerhans cell granulomatosis		Chronic	20−40 years old	Both	+	+	−	−	±	Dry	+	+	−	Unremarkable	−	−	Nonspecific	Mid to upper lung zone cysts and nodules Reticular and nodular opacities Recurrent spontaneous pneumothorax	↓ FEV1/FVC	Normal	>5 percent langerhans cells (CD−1a positive)	Lung biopsy
Pulmonary alveolar proteinosis		Acute/chronic	40−50 years old	Male	+	+	+	−	+	+	+	−	−	Inspiratory crackles	+	+	↑ LDH ↑ CEA ↑ Surfactant protein A, B, and D Anti-GBM antibody + Polycythemia Hypergammaglobulinemia	Bbilateral perihilar and basilar alveolar opacities without air−bronchograms "Bat wing" distribution Intralobular thickening Diffuse ground−glass opacities	↑ FEV1/FVC ↑ A−a gradient ↓ DLCO	↓ PaO2 ↓ O2 Respiratory alkalosis	Large foamy macrophages with amorphous PAS−positive material ↑ Lymphocytes	Bronchoscopy and BAL
Pulmonary lymphangioleiomyomatosis		Acute/chronic	30−40 years old	Female	+	+	−	−	+	Bloody	+	+	−	Decreased breath sounds	−	+	↑ Vascular endothelial growth factor−D (VEGF−D)	Pneumothorax Chylothorax Thin−walled round cystic lesions	↓ FEV1/FVC	↓ PaO2 ↓ O2	LAM cells +	Lung biopsy
Eosinophilic pneumonia		Acute/chronic	20−40 years old	Male	−	−	−	−	+	Dry	+	+	+	Decreased breath sounds	−	−	Neutrophilic leukocytosis ↑ Eosinophils Elevated ESR Elevated CRP Elevated IgE level	Bilateral diffuse mixed ground glass and reticular opacities Small bilateral pleural effusions Centrilobular nodules and air−space consolidation	↑ FEV1/FVC ↓ DLCO	↓ PaO2 ↓ O2	Eosinophilia	Clinical evaluation and investigations
Hypersensitivity pneumonitis		Acute/subacute/chronic	40−60 years old	Both	−	±	+	−	+	Dry/productive	+	+	+	Diffuse fine bibasilar crackles	−	+	Neutrophilic leukocytosis	Centrilobular ground−glass or nodular opacities of mid−to−upper zone  Air−trapping	↓ FEV1 ↓ FVC	↓ PaO2 ↓ O2	Lymphocytosis	Lung biopsy
Disease		History							Symptoms				Physical examination				Lab findings	Imaging	Pulmonary function test		Bronchoscopy and BAL	Gold standard
		Duration	Age	Gender	Family history	Smoking history	Environmental exposure	HIV	Dyspnea	Cough	Wheezing	Chest pain	Tachypnea	Auscultation	Cyanosis	Clubbing			Spirometry	ABG
Occupational lung disease		Chronic	Elderly	Male	+	+	+	−	±	+	+	+	+	Fine crackles	Peripheral/central	+	Anemia Neutrophilia Elevated ESR Elevated CRP Elevated immunoglobulin	Pleural thickening and plaques Calcification Nodular or reticular opacities Lobar consolidation Atelectasis Parenchymal bands Enlarged hilar or mediastinal lymph nodes Granulomata	↑ FEV1/FVC	↓ O2 ↑ CO2 Respiratory acidosis	Mineral dust +	History of environmental exposure and imaging Lung biopsy not required
Radiation−induced lung injury		Subacute/chronic	Any age	Both	−	−	+	−	+	Dry	+	+	+	Crackles Pleural rub Dullness to percussion	+	−	Nonspecific	Perivascular haziness to patchy alveolar filling densities Straight line effect Pleural effusion	↓ TLC ↓ FVC ↓ FEV1 ↓ DLCO	↓ PaO2 ↓ O2	Lymphocytosis	History of irradiation and clinical presentation
Pulmonary hemorrhage syndromes	Goodpasture syndrome	Chronic	All ages	Male	+	±	−	−	±	Bloody	±	−	−	Bilateral coarse crepitations	−	−	Anti-GBM antibody + ANCA + Anemia RBC in the urine	Pulmonary infiltrates	↑ DLCO	Normal	NA	Kidney biopsy
	Idiopathic pulmonary hemosiderosis	Acute/subacute/chronic	Children − 10 years old	Both	+	±	−	−	+	Bloody	+	+	−	Crackles	−	−	Iron deficiency anemia ↑ Plasma bilirubin ↑ Urinary excretion of urobilinogen ↑ Reticulocytes Fecal occult blood +	Mid to lower zone alveolar opacities Multiple honeycomb cysts	↓ TLC ↓ FVC ↓ FEV1 ↑ FEV1/FVC ↑ DLCO	↓ O2 ↓ CO2	↑ Hemosiderin−laden macrophages	Clinical evaluation and investigations
	Isolated pulmonary capillaritis	Chronic	40−60 years old	Both	+	−	±	−	+	Bloody	+	+	+	Decreased breath sounds	−	−	Anemia Leukocytosis	Diffuse alveolar haemorrhage	↓ FEV1/FVC	↓ O2	Diffuse alveolar haemorrhage	Diagnosis of exclusion
Disease		History							Symptoms				Physical examination				Lab findings	Imaging	Pulmonary function test		Bronchoscopy and BAL	Gold standard
		Duration	Age	Gender	Family history	Smoking history	Environmental exposure	HIV	Dyspnea	Cough	Wheezing	Chest pain	Tachypnea	Auscultation	Cyanosis	Clubbing			Spirometry	ABG
Sarcoidosis		Acute/subacute/chronic	20−40 years old	Female	+	±	−	−	±	+	+	±	−	Crackles Wheezing Decreased breath sounds	+	−	Hypercalciuria  Hypercalcemia High ACE Hypergammaglobulinemia	Hilar adenopathy Reticular opacities Pneumothorax Pleural thickening Chylothorax Pulmonary hypertension	↓ TLC ↓ FVC ↓ FEV1 ↑ FEV1/FVC ↓ DLCO	↓ O2 ↓ CO2 Respiratory acidosis	Lymphocytosis  Elevated adenosine deaminase D-dimer +	Clinical evaluation and investigations
Granulomatous vasculitides	Granulomatosis with polyangiitis (Wegener)	Chronic	Elderly	Both	+	−	−	−	+	+	+	±	−	Crackles	−	−	ANCA + Anemia Leukocytosis Thrombocytosis Elevated ESR Elevated CRP Elevated creatinine Urine protein + Hematuria	Cavitate nodules Ground−glass opacity Consolidation Pleural effusion Hilar adenopathy	↓ FEV1/FVC	↓ O2	Alveolar hemorrhage	Lung biopsy
	Eosinophilic granulomatosis with polyangiitis (Churg Strauss)	Chronic	40−50 years old	Both	+	−	−	−	−	+	+	−	−	Scattered wheezing	−	−	Eosinophilia Elevated IgE titers ANCA +	Areas of parenchymal opacification Mixed interstitial patchy alveolar opacities	↓ TLC ↑ RV	Normal	Eosinophilia	Lung biopsy
Bronchocentric granulomatosis		Chronic	30−70 years old	Both	−	−	−	−	±	±	+	±	−	Scattered wheezing	−	−	Eosinophilia Elevated IgE titers Elevated circulating IgE antibodies to Aspergillus species	Upper zone single or multiple pulmonary nodules  Consolidation Atelectasis	↓ FEV1/FVC	Normal	Eosinophilia	Lung biopsy
Pulmonary lymphomatoid granulomatosis		Chronic	30−50 years old	Male	−	−	−	−	+	+	+	+	−	Normal	−	−	Epstein-Barr virus (EBV) serology +	Mid to lower zone multiple poorly defined nodules Diffuse reticular abnormalities	Normal	↓ O2 Chronic respiratory alkalosis	Normal	Lung biopsy
Amyloidosis		Subacute/chronic	50−70 years old	Male	+	−	−	−	−	Bloody	+	−	−	Crackles	−	−	Congophilia with apple−green birefringence under polarized light	Tracheobronchial infiltration Persistent pleural effusions Parenchymal nodules	↓ FEV1/FVC	↓ O2	Normal	Lung biopsy
Disease		History							Symptoms				Physical examination				Lab findings	Imaging	Pulmonary function test		Bronchoscopy and BAL	Gold standard
		Duration	Age	Gender	Family history	Smoking history	Environmental exposure	HIV	Dyspnea	Cough	Wheezing	Chest pain	Tachypnea	Auscultation	Cyanosis	Clubbing			Spirometry	ABG

Laboratory Finidngs

There are multiple laboratory tests that may be helpful to ascertain or rule out the diagnosis of interstitial lung disease.

Condition	Disease	Investigation
All patients with suspicious interstitial lung disease		Complete blood count and differential
		Liver function tests	Alanine aminotransferase (ALT, SGPT)
			Aspartate aminotransferase (AST, SGOT)
			Alkaline phosphatase
		Renal function tests	Urinalysis
			Blood urea nitrogen (BUN)
			Creatinine (Cr)
Suspicious of systemic rheumatic disease	RA	Serology	Anti−cyclic citrullinated peptide (Anti-CCP)
	SLE	Serology	Anti−double stranded DNA antibodies (Anti-dsDNA antibody)
	Amyopathic dermatomyositis	Serology	Anti-melanoma differentiation-associated gene 5 (MDA-5)
	Nonspecific	Serology	Antinuclear antibody (ANA)
		Serology	Rheumatoid factor (RF)
		Serology	Anti-neutrophil cytoplasmic antibody (ANCA)
		Enzyme	Creatine kinase (CK), aldolase
Mechanic hands	Myositis	Myositis−associated antibodies	Anti-tRNA synthetases Jo-1
			Anti-tRNA synthetases PL-7
			Anti-tRNA synthetases PL-12
Sicca features or positive anti−extractable nuclear antigen (ENA)	Sjögren’s syndrome	Serology	Anti-RO (SS−A)
		Serology	Anti-La (SS−B)
	Mixed connective tissue disease	Serology	Anti-ribonucleoprotein (RNP)
	IgG4-related disease	Serology	Serum IgG4
Severe GERD or sclerodactyly	Limited systemic scleroderma	Serology	Anti-centromere
	Systemic scleroderma	Serology	Anti-topoisomerase I (anti-Scl-70)
Dyspnea	Heart failure	Enzyme	Brain natriuretic peptide (BNP)
	Pulmonary hypertension		N-terminal proBNP (NT-proBNP)
Anemia and/or hemoptysis	Coagulopathies	Coagulation studies
	Goodpasture syndrome	Serology	Anti−glomerular basement membrane (GBM) antibodies
	Antiphospholipid syndrome	Serology	Antiphospholipid antibodies
	Idiopathic pulmonary hemosiderosis	Serology	Serum IgA endomysial or tissue transglutaminase antibodies
Mediastinal lymphadenopathy	Multiple myeloma	Serum protein electrophoresis
Beryllium exposure	Berylliosis	Peripheral blood beryllium lymphocyte proliferation test
Risk factors for HIV	HIV	ELISA
		Western blot test

Occupational Lung Disease

• Occupational lung diseases are caused by the accumulation of different dust particles in the alveolar space.
• As the particles accumulate, the elimination mechanisms of the body begin to fail, resulting in activation of chemotactic factors that exacerbate the inflammatory response, and subsequently lead to fibrosis. 
• The most common particles that cause pneumoconiosis are asbestos, silica, coal, magnesium silicate, aluminum silicate, bauxite, cobalt, beryllium and iron.

For more information about occupational lung disease, click here.

Drug-induced lung injury

More than 600 medications have pulmonary toxicity and may cause lung injury.

• Lung injury following medication intake might vary from interstitial lung disease to hypersensitivity pneumonitis, pleural effusion or pulmonary edema.
• The presentation of lung injury might be acute, subacute or chronic and it might occur weeks to years even after discontinuing the drug.
• Diagnosis of drug-induced lung injury is by the exclusion of other diseases. Detailed history and paraclinical pulmonary investigations are required to exclude other causes of interstitial lung disease. Pulmonary investigations are as follow:
  • Restrictive pattern on pulmonary function tests (PFTs)
  • FEV1/FVC ratio normal or increased
  • Reduced DLCO
  • Bronchoalveolar lavage may exclude infectious disease
  • Bronchoscopy with transbronchial biopsy may be indicated to exclude other pulmonary diseases
  • Invasive lung biopsy rarely required
• Management of drug-induced lung injury includes:
  • Immediate drug discontinuation
  • Supportive therapy
  • Control of other underlying chronic pulmonary disease
  • Treatment of respiratory infections
  • Smoking cessation
  • Glucocorticoid therapy
• List of medications that might cause interstitial lung disease is as follow:

Drug−induced lung injury
Antimicrobial Agents	Anti−Inflammatory Agents	Biological Agents	Cardiovascular Agents	Immunomodulator agents	Antineoplastic agents	Miscellaneous
Amphotericin B Doripenem Ethambutol Isoniazid Minocycline Nitrofurantoin Sulfasalazine	Abatacept  Aspirin Azathioprine Cyclophosphamide Gold Anakinra Leflunomide Methotrexate Nonsteroidal anti-inflammatory drugs Penicillamine Sulfasalazine Thalidomide	Adalimumab Alemtuzumab Alpha interferon Bevacizumab Cetuximab Etanercept  Infliximab Panitumumab Rituximab Tocilizumab Trastuzumab	ACE inhibitors Amiodarone Anticoagulants Beta blockers Flecainide Hydrochlorothiazide Procainamide Statins Tocainide	Sirolimus Riluzole Trametinib vandetanib	Azathioprine Bleomycin Bortezomib Busulfan Carmustine (BCNU) Chlorambucil Colony-stimulating factors Crizotinib Cyclophosphamide Cytarabine Deferoxamine Docetaxel Doxorubicin Eribulin Erlotinib Etoposide (VP−16) Fludarabine Flutamide Gefitinib Gemcitabine Hydroxyurea Imatinib Lomustine (CCNU) Melphalan Mitomycin-C Nilutamide Nitrosourea Olsalazine Paclitaxel Procarbazine Semustine (Methyl−CCNU) Sorafenib Vinblastine	Bacille Calmette-Guerin (BCG) Bromocriptine Carbamazepine Cabergoline Cocaine Methysergide L-tryptophan Penicillamine Phenytoin Talc

Radiation-induced Lung Injury

Radiation has been considered as one of the causes of lung injury. About 5 to 15% of patients receiving radiation therapy may present with pulmonary symptoms.

• Pulmonary injury following irradiation is directly related to duration and dose of radiation.
• The main pathogenesis of radiation-induced lung injury is the damage to the type I pneumocytes which triggers the initiation of reactions. It leads to secretion of growth factors and proteases which increases degradation of extracellular matrix. Also, radiation causes damage to epithelial cells which leads to loss of barrier function. All of these changes cause a cycle of inflammation and fibrosis.
• There are two types of reaction in pulmonary tissues to radiation which include:
  • Early pulmonary reaction:
    • It usually occurs in 4 to 12 weeks following irradiation.
    • Early reaction mostly presents as radiation pneumonitis.
    • Treatment of radiation pneumonitis include steroids, ACE inhibitors and pentoxifylline.
  • Late pulmonary reaction:
    • It usually occurs 6 to 12 months following irradiation.
    • Late response usually induces lung fibrosis.
    • Management of lung fibrosis consists of supportive therapy, airway secretions mobilization, anti-inflammatory therapy, and management of acute exacerbations.
• CT might be used for the diagnosis of radiation pneumonitis. Ground glass opacities, consolidation, fibrosis, atelectasis, pulmonary volume loss, or pleural thickening might be seen on CT scan.

Smoking related Interstitial Lung Disease

Cigarette smoking may cause various adverse effects on pulmonary tissue.

• Cigarette smoke might injure alveolar epithelial cells leading to in diffuse infiltration and subsequently parenchymal fibrosis.
• Alveolar epithelial cells are the primary cells involved in the pathogenesis of emphysema as well as lung fibrosis following smoking.
• Cigarette smoking may predispose alveolar epithelial cells to cellular senescence and apoptosis that leads to emphysema or lung fibrosis.
• A well-known association exists between tobacco smoking and some types of interstitial lung disease such as:
  • Desquamative interstitial pneumonia
  • Respiratory bronchiolitis-associated interstitial lung disease
  • Pulmonary Langerhans cell granulomatosis
  • Acute eosinophilic pneumonia

Idiopathic Interstitial Pneumonia

The idiopathic interstitial pneumonias (IIP) are a broad range of interstitial lung diseases of unknown etiology.

• Pathogenesis of idiopathic interstitial pneumonia is fibroblasts proliferation and collagen deposition leading to inflammation and fibrosis.
• Patients with idiopathic interstitial pneumonia generally manifest as a gradual dyspnea and dry cough.
• On chest imaging it is characterized by bilateral abnormal opacities of various types.
• The most common type of idiopathic interstitial pneumonia is chronic idiopathic pulmonary fibrosis. However, acute interstitial pneumonia has the worst prognosis.
• The exact diagnosis can only be reached with a multidisciplinary approach after excluding known causes.
• The new classification of idiopathic interstitial pneumonias is as follow:
  • Major idiopathic interstitial pneumonias
    • Idiopathic pulmonary fibrosis
    • Idiopathic nonspecific interstitial pneumonia
    • Respiratory bronchiolitis-interstitial lung disease
    • Desquamative interstitial pneumonia
    • Cryptogenic organizing pneumonia
    • Acute interstitial pneumonia
  • Rare idiopathic interstitial pneumonias
    • Idiopathic lymphoid interstitial pneumonia
    • Idiopathic pleuroparenchymal fibroelastosis
  • Unclassifiable idiopathic interstitial pneumonias

For more information about Idiopathic interstitial pneumonia, click here.

For more information about idiopathic pulmonary fibrosis, click here.

For more information about Cryptogenic organizing pneumonia, click here.

Pulmonary Alveolar Proteinosis

Pulmonary alveolar proteinosis (PAP) is a rare lung disease that is characterized by the intra-alveolar accumulation of surfactant phospholipid and apoproteins.

• The exact etiology of pulmonary alveolar proteinosis is unknown.
• The primary pathogenesis of pulmonary alveolar proteinosis involves reduction in granulocyte-macrophage colony-stimulating factor (GM-CSF) levels or function and/or impaired alveolar macrophage function.
•  Terminal bronchioles and alveoli are filled with a lipoproteinaceous material that will be periodic acid-Schiff (PAS) stain positive.
• If left untreated, patients with pulmonary alveolar proteinosis may progress to develop pulmonary fibrosis or cor pulmonale.

For more information about pulmonary alveolar proteinosis, click here.

Lymphocytic Infiltrative Disorders

Lymphocytic infiltrative disorders might cause interstitial lung disease in mostly HIV positive children.

• The etiology of lymphocytic infiltrative disorders is unknown. However, there is an evidence of infectious cause such as EBV in HIV positive patients.
• The two main manifestations of lymphocytic infiltrative disorders include:
  • Lymphocytic interstitial pneumonitis
  • Pulmonary lymphomatoid granulomatosis

For more information about lymphocytic interstitial pneumonitis, click here.

Pulmonary Lymphangioleiomyomatosis

Lymphangiomyocytosis (LAM) is defined as a multifocal neoplasm with differentiation of the perivascular epithelioid cell that involves multiple organs.

• Lymphangiomyomatosis is the result of disorderly smooth muscle proliferation throughout the bronchioles, alveolar septa, perivascular spaces, and lymphatics, resulting in the obstruction of small airways (leading to pulmonary cyst formation and pneumothorax) and lymphatics (leading to chylous pleural effusion).
• LAM occurs in a sporadic form, which only affects females, who are usually of childbearing age.

For more information about pulmonary lymphangioleiomyomatosis, click here.

Pulmonary Hemorrhage Syndromes

Pulmonary hemorrhage syndromes might cause interstitial lung disease.

• Several pulmonary hemorrhage syndromes that affect the lung parenchyma and eventually lead to pulmonary fibrosis. Some of these are as follows:
  • Goodpasture syndrome
  • Idiopathic pulmonary hemosiderosis
  • Isolated pulmonary capillaritis

Interstitial Lung Disease Associated with Systemic Diseases

Interstitial lung disease associated with connective tissue diseases

• Systemic lupus erythematosus
• Rheumatoid arthritis
• Ankylosing spondylitis
• Systemic sclerosis
• Sjögren syndrome
• Polymyositis/dermatomyositis
• Granulomatosis with polyangiitis (Wegener's)
• Eosinophilic granulomatosis with polyangiitis (Churg Strauss)

Interstitial lung disease associated with inherited diseases

• Tuberous sclerosis
• Neurofibromatosis
• Niemann−Pick disease
• Gaucher disease
• Hermansky−Pudlak syndrome

Interstitial lung disease associated with gastrointestinal or liver diseases

• Crohn disease
• Primary biliary cirrhosis
• Chronic active hepatitis
• Ulcerative colitis

Interstitial lung disease associated with graft−versus−host disease

• Bone marrow transplantation
• Solid organ transplantation

Granulomatous Lung Response

• Hypersensitivity pneumonitis
• Sarcoidosis
• Granulomatous vasculitides
  • Granulomatosis with polyangiitis (Wegener)
  • Eosinophilic granulomatosis with polyangiitis (Churg Strauss)
• Bronchocentric granulomatosis

For more information about hypersensitivity pneumonitis, click here.

References