Interstitial lung disease
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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

# 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
- Inflammation and fibrosis pattern
- Granulomatous pattern

# 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: Creactive 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, Aa 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

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

# 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
- 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
- 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:

# 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.
- 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.
- 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.
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- Sjogren syndrome
- Polymyositis/dermatomyositis
- Granulomatosis with polyangiitis (Wegener's)
- Eosinophilic granulomatosis with polyangiitis (Churg Strauss)

## Interstitial lung disease associated with inherited diseases
- Tuberous sclerosis
- Neurofibromatosis
- NiemannPick disease
- Gaucher disease
- HermanskyPudlak 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 graftversushost 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)
- Granulomatosis with polyangiitis (Wegener)
- Eosinophilic granulomatosis with polyangiitis (Churg Strauss)
- Bronchocentric granulomatosis
For more information about hypersensitivity pneumonitis, click here.