Interstitial Lung Diseases

Interstitial lung diseases are a heterogeneous group of disorders characterized by the inflammation and fibrosis of lung parenchyma, especially the pulmonary connective tissue in the alveolar walls. It may be idiopathic (e.g., idiopathic pulmonary fibrosis) or secondary to connective tissue diseases, medications, malignancies, occupational exposure, or allergens. Interstitial lung diseases commonly present with progressive exertional dyspnea and dry cough. Pulmonary function testing shows a restrictive lung disease pattern. Lung high-resolution computed tomography and biopsy usually establish the diagnosis. Treatment includes steroids and immunosuppressives.

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Overview

Definition

  • Interstitial lung disease (ILD) comprises a heterogeneous group of disorders that cause varying degrees of inflammation and fibrosis of the lung interstitium, the space between the capillary endothelium and the alveolar epithelium.
  • Clinically, affected patients will show restrictive lung disease by pulmonary function studies.

Epidemiology

Idiopathic pulmonary fibrosis, sarcoidosis, and ILD associated with connective tissue diseases are the most common types of ILD.

Classification

It is useful to categorize ILDs into those with and without a known cause.

Table: Types of interstitial lung disease
Cause unknownCause known
Idiopathic interstitial pneumonias (IIP):
  • Idiopathic pulmonary fibrosis (IPF)
  • Nonspecific interstitial pneumonia (NSIP)
  • Cryptogenic organizing pneumonia (COP)
  • Acute interstitial pneumonia (AIP)
Smoking-related ILD:
  • Respiratory bronchiolitis-associated interstitial pneumonia (RB-AIP)
  • Desquamative interstitial pneumonia (DIP)
Other:
  • Lymphangioleiomyomatosis (LAM)
Systemic diseases
  • Connective tissue diseases (CTD)
    • Rheumatoid arthritis (RA)
    • Systemic lupus erythematosus
    • Systemic sclerosis
    • Sjogren’s disease
    • Dermatomyositis/polymyositis
  • Granulomatous disease
    • Granulomatosis with polyangiitis
    • Churg-Strauss disease
    • Pulmonary Langerhans cell histiocytosis (PLCH)
    • Sarcoidosis
    • Hypersensitivity pneumonitis (HP)
Exposure-related
  • Occupational
    • Asbestosis
    • Silicosis
    • Gases/fumes
  • Pharmacologic:
    Radiation, methotrexate, azathioprine, rituximab, tumor-necrosis factor blockers, amiodarone, nitrofurantoin, chemotherapeutics

Diagnosis

History

Age
  • IPF is rare in patients < 50 years
  • Sarcoidosis, CTD-associated ILD, and LAM are common between the ages of 20 and 40 years
Sex
  • LAM and CTD-associated ILD, except rheumatoid arthritis-associated ILD, are frequently found in women
  • IPF and occupational ILDs are more common in men
Clinical presentation
  • Acute onset (days to weeks): eosinophilic pneumonia, acute interstitial pneumonia, hypersensitivity pneumonitis, granulomatosis with polyangiitis, acute exacerbation of IPF
  • Subacute onset (weeks to months) and especially chronic onset (months to years): most other ILDs, especially IPF
Symptoms
  • Progressive exertional dyspnea (most common)
  • Dry cough (very common)
  • Fatigue (common)
  • Chest pain (uncommon; suggests sarcoidosis)
  • Hemoptysis (rare; suggests vasculitis, LAM)
Past medical history
  • CTD or symptoms of CTD such as Raynaud’s phenomena
  • Malignancy, which may indicate dermatomyositis-associated ILD
  • Asthma may suggest eosinophilic granulomatosis with polyangiitis (also known as Churg-Strauss)
Drug historyMethotrexate, azathioprine, rituximab, tumor-necrosis factor blockers, amiodarone, nitrofurantoin, chemotherapeutics
Family historyHaving a close relative with IIP is a strong risk factor for ILD, especially IPF.
Social history
  • Smoking history is present in almost all cases of DIP and the majority of IPF patients.
  • Exposure history such as to asbestos or birds (HP)

Physical examination

  • End-inspiratory fine crackles in lung bases (common finding, especially in IPF)
  • Wheezing is uncommon (may be found in HP, Churg-Strauss disease, sarcoidosis)
  • Severe disease findings: cyanosis, digital clubbing, cor pulmonale

Laboratory studies

Autoantibody detection may help with the diagnosis of some CTDs.

Pulmonary function testing

  • The diffusing capacity for carbon monoxide (DLCO) shows reduction.
  • Most show a restrictive pattern.

Imaging

  • Chest X-ray may be suggestive of a type of ILD:
    • Peripheral reticular pattern in lower lung zones and small cystic spaces suggests IPF.
    • Central nodular pattern in mid-to-upper lung zones and hilar lymph node enlargement suggests sarcoidosis.
  • Chest computed tomography (CT):
    • Standard initial test
    • May confirm the diagnosis of IPF in the right setting and obviate the need for lung biopsy
    • Better defines disease extent and features (e.g., honeycombing)
    • Helps exclude comorbidities (e.g., pneumothorax) or differential diagnosis (e.g., malignancy)
    • Helps determine the best location for biopsy

Lung biopsy

  • Establishes the diagnosis
  • Performed via fiberoptic bronchoscopy or surgery
  • Biopsy is not needed if:
    • High-resolution CT (HRCT) shows classic usual interstitial pneumonia and the patient has no systemic diseases suggestive of an another disorder.
    • Patient has minimal signs or symptoms and a stable/nonprogressive disease.
  • Indicated in cases of comorbidities or rapidly progressive symptoms

Individual Forms

Idiopathic pulmonary fibrosis

  • Most common ILD of unknown cause
  • Commonly diagnosed in 5th or 6th decade
  • Affects men more than women
  • Frequently associated with smoking
  • 35-year survival rate is 50%.
  • May be associated with acute exacerbations
  • Lung HRCT shows a pattern of UIP: subpleural reticular pattern with posterior-basal predominance with more advanced fibrotic features such as honeycombing and traction bronchiectasis.
  • Histopathology shows a pattern of UIP: subpleural reticulation, honeycombing, fibroblasts, skipped lesions with preserved architecture (temporal and spatial heterogeneity).
  • Treatment: physical therapy and supplemental oxygen, antifibrotic therapy (pirfenidone), and lung transplantation if patient meets criteria

Non-specific interstitial pneumonia

  • May be idiopathic or commonly associated with CTDs
  • Commonly diagnosed in non-smoking women in their 5th decade
  • 5-year survival rate is 80%.
  • Lung HRCT shows diffuse and symmetric subpleural ground-glass and reticular opacities; traction bronchiectasis may be seen; honeycombing and peribronchial thickening is uncommon.
  • Histopathology shows uniform interstitial inflammation and fibrosis without honeycombing.
  • Treatment: physical therapy, supplemental oxygen, steroids, immunosuppressive therapy, and lung transplantation if patient meets criteria

Cryptogenic organizing pneumonia

  • May be idiopathic or secondary to polymyositis, medications, or malignancy
  • Commonly diagnosed in 6th or 7th decade
  • Lung HRCT shows migratory, patchy, subpleural consolidations and ground-glass opacities with or without a rim of subpleural sparing known as the halo sign (characteristic).
  • Treatment: steroids and immunosuppressives

Smoking-related ILD

  • Occurs in heavy smokers in the 5th or 6th decade
  • Honeycombing is typically absent
  • Biopsy confirms diagnosis
  • Treatment includes smoking cessation and immunosuppressive therapy

Connective tissue disease–associated ILD and granulomatous ILD

Table: Typical features of systemic sclerosis (a common cause of CTD–associated ILD), sarcoidosis (most common granulomatous ILD), and IPF (most common idiopathic ILD)
IPFSystemic sclerosis–associated ILDSarcoidosis
SymptomsOlder adult with gradual shortness of breath and dry coughGradual shortness of breath and dry cough, fatigue, skin tightening, Raynaud’s phenomenon, reflux, dysphagiaAsymptomatic or with gradual shortness of breath and cough, fatigue, palpitations, joint pain, eye and skin involvement
SignsCrackles at lung bases and digital clubbingCrackles, skin thickening and joint swelling, telangiectasiasNone or crackles, skin findings, joint swelling, lymphadenopathy
ExposuresTobacco smokeMostly unknownMostly unknown
HRCT
  • Bilateral peripheral reticular pattern in lower posterior lung zones
  • Honeycombing
  • Tractional bronchiectasis
  • UIP pattern is diagnostic.
UIP or NSIP pattern, dilated esophagus, pulmonary vascular dilationMediastinal/hilar lymphadenopathy, reticulonodular peribronchiovascular involvement
HistopathologyUIP pattern (fibroblastic foci, honeycombing, spatial heterogeneity)NSIP pattern with occasional UIP featuresNon-caseating granuloma
Clinical course3–5 year survival: 50%10-year survival: 70%–80%Overall good survival

Complications

  • Acute exacerbations of IIPs:
    • Accelerated phase of lung injury in a patient with an underlying ILD
    • Acute onset (< 30 days) of respiratory distress and hypoxemia more severe than what was previously experienced by the underlying ILD and not explained by other causes (e.g., pneumonia, heart failure)
    • Most commonly described in IPF
    • Lung HRCT shows a change in the pattern previously observed due to the underlying ILD with patchy bilateral ground-glass opacities and consolidation in dependent regions.
    • Histopathology shows diffuse alveolar damage.
    • Treatment is supportive as no proven therapy exists; lung transplantation may provide cure.
    • Mortality rate > 85%
  • Pulmonary hypertension
  • Pneumonia
  • Ischemic heart disease
  • Thromboembolic disease
  • Lung cancer

Differential Diagnosis

  • Cardiovascular disease (e.g., heart failure)
  • Diffuse infections (e.g., pneumocystis pneumonia)
  • Malignancy (e.g., bronchoalveolar cell carcinoma):
    • Note that ILDs such as COP may occur secondary to dermatomyositis and malignancy; however, lung malignancies such as bronchoalveolar cell carcinoma can mimic the symptoms and signs of ILD.

References

  1. Kasper DL, Fauci AS, Hauser SL, Longo DL, Lameson JL, Loscalzo J. Harrison’s Principles of Internal Medicine. New York, NY: McGraw-Hill Education; 2018.
  2. King TE, Raj R. Role of lung biopsy in the diagnosis of interstitial lung disease, in UpToDate Evidence-Based Medicine. Retrieved on August 18, 2020, from https://www.uptodate.com/contents/role-of-lung-biopsy-in-the-diagnosis-of-interstitial-lung-disease?search=interstitial-lung-disease&topicRef=4310&source=see_link#H4256910517

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