Summary
Interstitial lung diseases (ILDs) are a heterogeneous group of disorders characterized by inflammation and progressive scarring (fibrosis) of the lungs. ILDs can be idiopathic (i.e., idiopathic interstitial pneumonias) or secondary to known causes such as autoimmune disease, changes in response to medical treatment, and diseases caused by exposure to radiation and inhalation of harmful substances. ILDs can lead to irreversible fibrosis and impaired pulmonary function. Cough and progressive exertional dyspnea are the most common symptoms. Bibasilar inspiratory crackles or rales are usually heard on auscultation. The treatment involves immune modulators, corticosteroids, and, in idiopathic pulmonary fibrosis, antifibrotic therapy (e.g., pirfenidone, nintedanib). Advanced stages of ILD can result in pulmonary insufficiency and respiratory heart failure with right ventricular insufficiency.
Definition
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Interstitial lung diseases (ILDs)
- A term encompassing a heterogeneous group of disorders characterized by inflammation and progressive fibrosis of the lungs.
- Cough and progressive exertional dyspnea are the most common symptoms. [1]
- Idiopathic interstitial pneumonias (IIPs): a group of interstitial lung diseases of unknown cause, also described as diffuse parenchymal lung diseases (DPLDs), characterized by inflammation and fibrosis of the pulmonary interstitium but frequently also affect the airspaces, peripheral airways, and vessels
- Pneumoconioses: a group of restrictive interstitial lung diseases caused by the inhalation of certain substances (mainly dusts) that often affect miners and agricultural workers
Etiology
Idiopathic interstitial pneumonias (IIPs)
- Idiopathic pulmonary fibrosis (IPF)
-
Other IIPs
- Acute interstitial pneumonia (AIP)
- Cryptogenic organizing pneumonia (COP)
- Respiratory bronchiolitis-associated interstitial lung disease (RB-ILD)
- Desquamative interstitial pneumonia (DIP)
- Nonspecific interstitial pneumonia (NSIP)
- Lymphoid interstitial pneumonia (LIP)
- Idiopathic pleuroparenchymal fibroelastosis
Secondary to a known cause
Exposure-related (environmental and occupational)
- Hypersensitivity pneumonitis (extrinsic allergic alveolitis)
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Pneumoconioses
- Coal worker's lung
- Asbestosis
- Silicosis
- Berylliosis
- Radiation pneumonitis
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Substance-induced ILD
- Chemotherapeutic agents
- Other medications
- Other substances
Secondary to underlying disease
- Connective tissue diseases
- Granulomatous diseases: sarcoidosis
- Vasculitis
- Hypersensitivity reactions: eosinophilic pneumonia
- Alveolar filling diseases
- Infectious diseases
- Miscellaneous
Classification of idiopathic interstitial pneumonias
Idiopathic pulmonary fibrosis (IPF)
- Definition: most common type ILD, characterized by irreversible pulmonary fibrosis and impaired pulmonary function
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Epidemiology
- Incidence: 10:100,000 cases per year [2]
- Affects mostly men 50–70 years of age
-
Diagnosis [3]
- Requires the absence of other known causes of interstitial lung disease (e.g., medication, environmental exposures, connective tissue disease)
- Presence of usual interstitial pneumonia (UIP) pattern on HRCT or histopathological studies
- Honeycomb appearance with or without traction bronchiectasis
- Ground-glass opacification with superimposed reticular abnormalities
- Bibasal subpleural distribution
- Prognosis: Respiratory failure usually occurs within 3–7 years.
Acute interstitial pneumonia (AIP)
- Definition: a severe, acute ILD that can rapidly progress to respiratory failure
- Epidemiology: most commonly affects individuals without preexisting lung conditions
- Diagnostics: histologically characterized by diffuse alveolar damage
Cryptogenic organizing pneumonia (COP)
- Definition: a rare, type of ILD characterized by inflammation of the bronchioles, alveolar ducts, and alveolar walls
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Epidemiology
- Incidence: 1–3 per 100,000 hospital admissions [4]
- Affects mostly individuals 40–50 years of age
- Diagnostics: histologically characterized by the presence of Masson bodies (granulation tissue buds made of foamy macrophages, mononuclear cells, and fibrous tissue) and chronic patchy interstitial inflammation without fibrosis
Nonspecific interstitial pneumonia (NSIP)
- Definition: a type of ILD characterized by a mild to moderate chronic interstitial inflammation, without specific histopathologic findings that characterize UIP
- Epidemiology: affects nonsmoker women 50–60 years of age
- Etiology: associated with connective tissue diseases (e.g., systemic sclerosis), HIV infection, and hypersensitivity pneumonitis
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Diagnostics
- Immediate subpleural sparing on imaging studies is considered specific for NSIP.
- Histological findings include interstitial thickening due to fibrosis and/or inflammatory cells
Desquamative interstitial pneumonia (DIP)
- Definition: a rare type of ILD characterized by lung inflammation due to intraalveolar mononuclear infiltration
- Epidemiology: affects men 40–50 years of age with a history of smoking
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Diagnostics
- Imaging studies show ground-glass opacities in the lower pulmonary lobes, usually without peripheral reticular opacities
- Histologically characterized by intraalveolar accumulation of macrophages and thickening of alveolar septa
Respiratory bronchiolitis-interstitial lung disease (RBILD)
- Definition: a rare, mild ILD characterized by bronchiolar inflammation
- Epidemiology: affects individuals 30–50 years of age with a history of smoking
- Diagnostics: histologically characterized by accumulation of brown pigmented macrophages and bronchiolar submucosal inflammation
Lymphocytic interstitial pneumonia (LIP)
- Definition: a rare ILD characterized by lymphocytic infiltration of the alveolar and alveolar septa
- Epidemiology: affects adults (especially women) of all ages
- Etiology: Associated with autoimmune (e.g., Sjögren disease, SLE) disorders, lymphoproliferative disorders, and HIV infection
- Diagnostics: histologically characterized by diffuse alveolar and interstitial infiltration with plasma cells and polyclonal lymphocytes
Idiopathic pleuroparenchymal fibroelastosis (IPPFE)
- Definition: a rare ILD characterized by pleural and subpleural fibrosis
- Epidemiology: affects nonsmoker individuals between 50 and 60 years of age
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Diagnostics
- Imaging studies show pleural and subpleural thickening of the upper pulmonary lobes on imaging studies
- Histological findings include intraalveolar fibrosis and elastosis of the alveolar walls
Pathophysiology
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General
- All types of ILDs share the same basic pathophysiology.
- Repeated cycles of tissue injury in the lung parenchyma with aberrant wound healing → collagenous fibrosis → remodeling of the pulmonary interstitium [5]
- Pneumoconiosis: inhalation of dust particles →; phagocytosis by alveolar macrophages → destruction of alveolar macrophages, inflammatory reaction → scarring, granuloma formation
Clinical features
Features
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Progressive dyspnea
- Exertional dyspnea that progresses to dyspnea at rest
- Patients may present with high-frequency, shallow breathing to compensate for dyspnea. [6]
- Persistent nonproductive cough
- Bibasilar, inspiratory crackles or rales (velcro-like rales) on auscultation
- Fatigue
- Fever is common in hypersensitivity pneumonitis and sarcoidosis, but otherwise uncommon.
- Findings suggestive of connective tissue disease, sarcoidosis, or vasculitis
Advanced disease
- Digital clubbing due to chronic hypoxia
- Cyanosis
- Loud inspiratory wheeze
Diagnostics
Due to the wide variety of subtypes and symptoms, there is no universal diagnostic algorithm. Complete medical history, physical examination, serology, imaging (chest X-ray, CT scan), and pulmonary function tests should be performed in all patients with symptoms of ILD. Lavage and biopsy can help identify confounding conditions (e.g., infection, malignancy) and confirm the diagnosis of a given type or stage of ILD. [7]
Complete medical history
- Age and sex
- Past medical history (underlying conditions, medications, smoking history, irradiation history)
- Family history
- Occupational or Environmental exposure (symptoms depend on type, extent, and duration exposure)
Laboratory tests
- CBC
- LFTs
- BUN and creatinine
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Arterial blood samples
- Elevated alveolar-arterial partial pressure of oxygen gradient
- Decreased partial pressure of oxygen
- Screen for rheumatic and autoimmune diseases (e.g., rheumatoid factor, ANA, aldolase, anti-CCP, anti-Jo1)
- In case of suspected pulmonary hypertension or cor pulmonale: BNP or NT-proBNP
Imaging
Chest X-ray
- Normal in approx. 10% of patients
- Increase in reticular opacities (sign of fibrosis)
- Patients may have nodular or mixed patterns
- Ground-glass opacities
CT or HRCT
- Honeycombing: multiple cystic lesions within the lung parenchyma due to fibrosis
- Traction bronchiectasis: irreversible dilatation of the bronchi and bronchioles due to fibrosis
- Irregular thickening of the interlobular septa (smooth, nodular, or irregular)
- Specific patterns for ILDs may be specific to the underlying condition (e.g., hilar lymphadenopathy with or without bilateral reticular opacities in sarcoidosis, pleural plaques, and pleural reticulonodular opacities in asbestosis)
Pulmonary function tests (spirometry, lung volumes, diffusing capacity)
- Restrictive lung disease pattern (reduced lung volume, normal/decrease FEV1, decreased FVC, increased/normal FEV1/FVC ratio)
- Decreased diffusing capacity for CO (DLCO): highly sensitive parameter
Bronchoalveolar lavage [8]
- Indications
- Patients with acute and rapidly progressive respiratory symptoms
- Hemoptysis
- Infection
- Patients with sarcoidosis, hypersensitivity pneumonitis, IPF, or Langerhans cell histiocytosis
- Less invasive procedure than a lung biopsy
Surgical biopsy
- Indications
- Inconclusive initial evaluation
- Atypical or rapidly progressive symptoms
- Disease exacerbation
- Ambiguous pulmonary function tests
- In patients with minimal signs or symptoms and stable disease: close observation (e.g., PFTs, HRCTs over several months) may be sufficient.
Additional tests
- EKG and echocardiogram in case of suspected pulmonary hypertension or concomitant heart disease
References:[9][10]
Overview of pneumoconioses
Differential diagnoses of pneumoconioses [11][12] | ||||
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Type | Etiology | Population at risk | Clinical features | Chest x-ray |
Asbestosis |
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Silicosis |
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Aluminosis [13][14] |
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Anthracosis [15][16] |
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Coal workers' pneumoconiosis [15][16] |
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Berylliosis |
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Pulmonary siderosis [19][20] |
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Organic dust toxic syndrome |
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Byssinosis [21] |
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Although coal is mined from under the earth, the upper lobes of the lungs are primarily affected.
Treatment
Treatment choices and prognosis for ILD vary depending on type and cause.
General measures
- Smoking cessation (if applicable)
- Supportive care
- Antibiotics if bacterial interstitial pneumonia is suspected
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Lung transplantation
- Indicated in end-stage ILD
- Only definitive treatment
Further general measures not applicable to IPF
- Avoid or limit exposure to causative or exacerbating substances
- Cessation of therapy with causative medication
- Contain occupational/environmental exposure (e.g., with protective equipment)
- Bronchodilators
- Corticosteroids (hypersensitivity pneumonitis)
- Immune modulators (e.g., azathioprine and mycophenolate)
Idiopathic interstitial pneumonias
Idiopathic pulmonary fibrosis
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Antifibrotic agents [22][23][24]
- Pirfenidone: an antifibrotic agent that inhibits TGF-β stimulated collagen synthesis, decreases the extracellular matrix accumulation, and blocks PDGF effects in vitro
- Nintedanib: an intracellular inhibitor of tyrosine kinases that target fibrogenic growth factors (e.g., vascular endothelial growth factor receptor, fibroblast growth factor receptor, and platelet-derived growth factor receptor)
- Appear to slow disease progression in IPF
- Prevention of gastroesophageal reflux
Other idiopathic interstitial pneumonias
- Therapy varies by subtype.
- Corticosteroids and/or immune modulators
Complications
- Pulmonary hypertension
- Cor pulmonale
- Respiratory failure: initially partial respiratory failure (↓ pO2), followed by global respiratory failure (↑ pCO2) in advanced stages
We list the most important complications. The selection is not exhaustive.