Interstitial Lung Disease

Interstitial Lung Disease is a topic covered in the Washington Manual of Medical Therapeutics.

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General Principles

Definition

ILDs are a heterogeneous group of >200 disorders characterized by infiltration of the lung interstitium by cells, fluid, and/or connective tissue.

ILDs can present acutely or chronically, and they are often diagnosed using a multidisciplinary approach employing pulmonary clinicians, radiologists, and pathologists.

Classification

  • ILDs can be broadly classified into those with known causes and those without (idiopathic).
    • Idiopathic interstitial pneumonias:1
      • Idiopathic pulmonary fibrosis (IPF) (idiopathic usual interstitial pneumonia [UIP])
      • Idiopathic nonspecific interstitial pneumonia (NSIP)
      • Desquamative interstitial pneumonia (DIP)
      • Respiratory bronchiolitis–associated interstitial lung disease (RB-ILD)
      • Cryptogenic organizing pneumonia (COP) (idiopathic OP)
      • Acute interstitial pneumonia (AIP)
      • Lymphoid interstitial pneumonia (LIP) (rare)
      • Idiopathic pleuroparenchymal fibroelastosis (rare)
    • Medication/therapy induced:
      • Bleomycin
      • Amiodarone
      • Nitrofurantoin
      • Checkpoint inhibitors
      • NSAIDs
      • Thalidomide
      • Rituximab
      • Azathioprine
      • Methotrexate
      • Radiation therapy
    • CTD-ILD:
      • Rheumatoid arthritis
      • Scleroderma
      • Sjögren syndrome
      • Antisynthetase syndrome
      • Mixed CTD
      • Systemic lupus erythematosus
    • Vasculitides:
      • Granulomatosis with polyangiitis
      • Eosinophilic granulomatosis with polyangiitis
      • Microscopic polyangiitis
      • Goodpasture syndrome
    • Pneumoconiosis (diseases of the lung due to dust inhalation):
      • Coal miners’ pneumoconiosis
      • Asbestosis
      • Silicosis
      • Siderosis
      • Stannosis
      • Mixed dust pneumoconiosis
    • Granulomatous ILD:
      • Sarcoidosis
      • Berylliosis
      • Hypersensitivity pneumonitis (HP)
      • Granulomatous–lymphocytic interstitial lung disease
      • Bronchocentric granulomatosis
    • Cystic lung diseases:
      • Lymphangioleiomyomatosis (LAM)
      • Pulmonary Langerhans cell histiocytosis (PLCH)
      • Birt–Hogg–Dubé (BHD) syndrome
      • Pulmonary amyloidosis
      • Light chain deposition disease
      • Postinfectious
    • Miscellaneous:
      • Erdheim–Chester disease
      • Pulmonary alveolar proteinosis
      • Lipoid pneumonia
      • Pulmonary alveolar microlithiasis
      • Acute eosinophilic pneumonia
      • Chronic eosinophilic pneumonia

Clinical Presentation

History

  • Obtaining a thorough history is of paramount importance in patients presenting with ILD and is often crucial in making a diagnosis.
  • Patients most often present with progressive dyspnea and persistent dry cough.
  • Duration of symptoms may help in differentiating ILDs. While many ILDs present with years of progressive dyspnea and cough, a subset of ILD patients present with acute or subacute onset of symptoms (AIP, acute eosinophilic pneumonia, OP), which may mimic infectious pneumonias with atypical organisms.
  • Past medical history is very important, not only for underlying diseases but also to identify ILDs related to disease management. Examples include CTDs and immunosuppressive agents; cancers along with chemo-, immuno-, and radiotherapies; and other systemic diseases that can potentially affect the lungs such as inflammatory bowel disease. It is important not to forget the use of over-the-counter medications.
  • Documenting a smoking history is essential. Some ILDs manifest almost exclusively in smokers (Langerhans cell histiocytosis, DIP, and RB-ILD). Some diseases are strongly associated with current or previous tobacco use, for example, IPF. Pulmonary hemorrhage is far more common in active smokers with Goodpasture disease than in prior or nonsmokers.
  • Exposures both at home and in the workplace should be evaluated. These may include exposures to radiation, asbestos, metal dusts, wood dusts, chemicals or fumes, pets, moldy environments, down comforters and/or pillows, and more. Patients should be questioned regarding the degree and duration of their exposures, and the use of respiratory protective equipment.
  • Family history should be obtained, specifically as it relates to pulmonary fibrosis, lung disease, or autoimmune disease. Multiple inheritance patterns have been described with ILDs including complex (sarcoidosis), autosomal dominant (tuberous sclerosis), and autosomal recessive (Hermansky–Pudlak syndrome).

Physical Examination

  • Extrapulmonary examination in patients with ILD should pay particular attention to findings of systemic diseases that may affect the lungs. These include CTDs, sarcoidosis, tuberous sclerosis, and others.
    • Examples include sclerodactyly, mechanic’s hands, Raynaud phenomenon, dry mucous membranes, telangiectasias, skin rashes, facial erythema, papules, eczema, or other skin lesions.
  • Cardiac examination should focus on findings suggesting the presence of PH/cor pulmonale including a right ventricular heave, pulmonary artery tap, tricuspid regurgitation holosystolic murmur, right-sided S3, and peripheral edema. These findings are usually indicative of advanced lung disease.
  • Clubbing is a very nonspecific finding described in lung diseases, heart diseases, and gastrointestinal (GI) diseases. It can be seen in IPF, sarcoidosis, PLCH, and other ILDs.
  • The pulmonary examination in ILDs is nonspecific. Findings may include dry inspiratory crackles, which are best noted posteriorly near the lung bases. Wheezes and inspiratory squeaks may also be noted.

Diagnostic Testing

Diagnostic testing in the evaluation of ILDs typically involves:

  • Chest imaging including CXR and high-resolution CT (HRCT) of the chest
  • Pulmonary function tests (PFTs)
  • Blood testing
  • Lung sampling including bronchoscopy and video-assisted thoracic surgery (VATS)

Chest Imaging

  • Review of old CXRs is often very helpful in assessing both the rate and extent of change of lung disease over time.
  • Up to 10% of CXRs may be normal in patients with ILD; as a result, a normal CXR may not exclude ILD in settings where the clinical suspicion of ILD is very high.
  • As a result of the wide variety of ILDs, CXRs may have a highly variable appearance.
  • The most common abnormality on CXR in ILD is a reticular pattern of linear opacities that may be localized or form a network involving the lungs diffusely.
  • However, nodular opacities, alveolar opacities, mixed alveolar opacities, and reticular opacities and occasionally cystic changes are also seen.
  • Extensive fibrosis of the lungs may lead to volume loss in one or both lungs.
  • Patients with known or suspected ILDs should undergo CT scanning as the diagnosis of many ILDs relies on HRCT.2
  • HRCT is a scanning technique that uses thin slice (usually 1-mm thick) images that are obtained and processed using a high-frequency reconstruction algorithm.2 Scans are obtained with the patient in a supine position during a breath hold at maximal inspiration and then during a breath hold at maximal expiration.
  • Prone imaging may be performed in cases where atelectasis obscures the posterior lung bases.
  • The pattern on HRCT is important in determining the differential diagnosis of ILD (Table 10-6). Notably, published guidelines exist for the definitive radiologic diagnosis of certain ILDs, specifically IPF.2
Table 10-6: Clinical and Radiologic Features of Interstitial Lung Diseases

Clinical FeaturesHRCT Findings
UIP
  • Insidious onset and progressive dyspnea
  • Dry cough
  • Poorly responsive to treatment, poor long-term survival
  • Variable course punctuated by intermittent exacerbations
  • Pattern can be associated with connective tissue disease
  • Older patients >50 y
  • Male predominance
  • UIP on CT or biopsy forms the radiologic basis for diagnosing IPF in the absence of underlying cause
  • Subpleural, basal predominant reticulation/interstitial thickening
  • Honeycombing with/without traction bronchiectasis
  • Heterogeneous (geographic) distribution
  • Absence of ground glass, consolidation, micronodules, cysts, or air trapping
  • May have atypical distribution in familial cases
NSIP
  • Associated with younger patients
  • More common in females
  • Commonly associated with collagen vascular diseases, including scleroderma, rheumatoid arthritis, and antisynthetase syndrome
  • Response to therapy is variable depending on etiology
  • Interstitial thickening, often with peripheral subpleural sparing
  • Ground-glass infiltrates
  • Traction bronchiectasis
  • Homogeneous distribution
  • In end-stage disease, may develop fibrotic changes and “bronchiolectasis” that resembles UIP
RB-ILD
  • Associated with cigarette smoking
  • Generally responsive to smoking cessation
  • Bronchiolocentric ground-glass nodules with an upper lobe predominance
DIP
  • Associated with cigarette smoking and occupational exposures
  • Generally responsive to smoking cessation
  • May be treated with corticosteroids
  • Peripheral ground-glass opacities or consolidation
  • May have small, well-defined cysts
COP
  • Subacute course, often presents as multiple outpatient treatment failures of bronchitis/pneumonia
  • Often associated with infections or drug exposures
  • Responsive to prolonged courses of corticosteroids
  • Often recurs if steroids are withdrawn too rapidly
  • Multifocal ground-glass opacities and consolidations
  • Usually lower lobe predominant
  • Infiltrates may be migratory on serial imaging
  • May have “reverse halo” or atoll sign
Sarcoidosis
  • Dyspnea, cough, and chest pain are common presenting symptoms
  • Systemic symptoms may be prominent
  • Approximately 1 in 20 cases are asymptomatic and incidentally detected on CXR
  • Almost any organ system may be affected
  • Perilymphatic nodules
  • Patchy ground-glass opacities
  • Reticular infiltrates
  • Traction bronchiectasis
  • Progressive massive fibrosis
  • Hilar or mediastinal lymphadenopathy
Fibrotic HP/fibrotic HP with honeycombing
  • Presents in a similar fashion to UIP/IPF
  • There may be a history of systemic symptoms (fever, myalgias)
  • Associated with environmental exposures (birds, molds, hot tubs) but these are identified in <50% of cases
  • Reticular abnormality with an upper or mid-lung predominance
  • Micronodules
  • Mosaic attenuation/air trapping
  • Peribronchovascular predominance
  • Honeycombing may be present in more advanced disease

BAL, bronchoalveolar lavage; COP, cryptogenic organizing pneumonia; DIP, desquamative interstitial pneumonia; HP, hypersensitivity pneumonitis; HRCT, high-resolution CT; ILD, interstitial lung disease; IPF, idiopathic pulmonary fibrosis; NSIP, nonspecific interstitial pneumonia; RB-ILD, respiratory bronchiolitis–associated interstitial lung disease; UIP, usual interstitial pneumonia.

Data from Kadoch MA, Cham MD, Beasley MB, et al. Idiopathic interstitial pneumonias: a radiology-pathology correlation based on the revised 2013 American Thoracic Society-European Respiratory Society classification system. Curr Probl Diagn Radiol. 2015;44:15-25  [PMID:25512168]; Raghu G, Collard HR, Egan JJ, et al. An official ATS/ERS/JRS/ALAT statement: idiopathic pulmonary fibrosis – evidence-based guidelines for diagnosis and management. Am J Respir Crit Care Med. 2011;183:788-824  [PMID:21471066]; Webb RW, Higgins CB. Thoracic Imaging: Pulmonary and Cardiovascular Radiology. Lippincott Williams & Wilkins; 2005.

Pulmonary Function Testing

  • PFTs are a noninvasive set of tests that allow for evaluation of lung function, stratification of disease severity, and for monitoring of disease progression over time.
  • Complete pulmonary function testing involves spirometry, lung volumes, and diffusing capacity (DLCO), along with resting and exercise pulse oximetry.
  • PFTs allow us to determine whether patients have restrictive lung disease, obstructive lung disease, or a mixed pattern of disease. This aids in the differential diagnosis of ILD.
  • While most fibrotic ILDs demonstrate a restrictive pattern on PFTs, a number of ILDs may demonstrate obstruction, including smoking-related lung diseases (RB-ILD and PLCH), cystic lung diseases (LAM and BHD), and sarcoidosis.
  • DLCO is commonly decreased in patients with ILD but is a nonspecific finding.
  • In some cases, the presence of coexisting COPD in patients with ILDs may lead to a mixed pattern of lung disease on PFTs. In other cases, pseudonormalization of PFTs occurs where the combination of restriction and obstruction leads to the finding of “normal” testing. In these cases, a low DLCO may be the only clue that the patient has significant underlying lung disease when the PFTs are reviewed in isolation.
  • Resting and exercise pulse oximetry are commonly assessed using a 6MW test.
  • Serial PFTs obtained at follow-up visits are a useful way to monitor for disease progression and may have prognostic significance.3

Laboratories

  • Routine laboratory testing in the evaluation of ILD patients includes CBC, BMP, and LFT testing. These may provide clues to the diagnosis (eosinophilia).
  • Many drugs used in the treatment of ILD require regular monitoring of blood counts, renal function, or liver function.
  • Serologic testing for CTDs is obtained in all patients with clinical stigmata of CTD.
  • Aldolase and creatinine kinase may be tested to evaluate for evidence of myositis in patients with a clinical suspicion for antisynthetase syndrome. In cases where suspicion is high for myositis, panels of muscle-specific antibodies should also be obtained.
  • In any patient with a high suspicion for scleroderma or Sjögren disease, an ENA panel should be obtained. ENA panels vary but contain a wide variety of antibodies to screen for CTD.
  • In practice, serologic testing is often obtained in a wide range of patients to exclude subclinical CTD. Many centers obtain a minimum of an antinuclear antibody (ANA), rheumatoid factor, and a cyclic citrullinated peptide antibody tests, even patients with suspected IPF, since rheumatoid arthritis ILD often presents with a UIP pattern on HRCT.
  • In patients with cystic lung disease on imaging, testing for vascular endothelial growth factor type D (VEGF-D) may be helpful in making the diagnosis of LAM. Levels of VEGF-D > 800 pg/mL in the correct clinical or radiographic setting can be diagnostic of LAM.4
  • Genetic testing can also be helpful in cystic lung diseases and can screen for tuberous sclerosis–associated LAM (TSC1 and TSC2 gene mutations) and BHD (FLCN, folliculin gene mutations) where appropriate.

Lung Sampling

  • When an extensive evaluation does not result in a confident diagnosis, lung sampling can be considered.
  • Bronchoalveolar lavage (BAL) is used to sample the cellular content of the lungs. It has limited utility in the evaluation of ILD.
  • BAL is useful in excluding coexisting infection and, in some cases, malignancy. It is also useful in cases where diffuse alveolar hemorrhage or eosinophilic lung disease is suspected.5
  • Lung biopsy should only be undertaken at centers with expertise in evaluating ILD patients. Generally, biopsy should be reserved for circumstances where the diagnosis is uncertain and clarification would result in a significantly altered approach to management.
  • While lung biopsy is desired in many cases, patients with ILD are often considerably physiologically impaired and may not tolerate the procedure.
  • Although many patients tolerate lung biopsy well, certain subgroups of patients are predisposed to complications, including decompensation of their ILD following lung biopsy.6 Patients with IPF may develop disease exacerbations following lung biopsy, resulting in disease progression and even death.
  • Two types of lung biopsy are available: transbronchial forceps biopsy (TBBx) and VATS biopsy.
  • TBBx is often performed along with BAL during bronchoscopy. It is most useful in cases in which small biopsy samples suffice for diagnosis.
  • TBBx has the highest yield in bronchiolocentric ILDs, such as sarcoidosis, berylliosis, and lymphangitic carcinomatosis.7 It is also useful in cases where eosinophilic pneumonia or pulmonary alveolar proteinosis is suspected.
  • TBBx is insufficient for differentiating most idiopathic ILDs, especially between UIP and NSIP, given inadequate sample size.
  • However, a recently developed test, the Envisia Genomic Classifier, uses genomic patterns in TBBx samples to distinguish UIP fibrotic lung disease from non-UIP fibrotic lung disease. It is may helpful in well-selected patients with lung fibrosis who would not tolerate VATS biopsy.
  • Transbronchial cryobiopsy is a newer option that allows for larger volume tissue sampling without a surgical lung biopsy. Further studies are required to integrate this technique into the ILD diagnostic algorithm.8
  • In cases with UIP patterns, VATS biopsies are preferred as they yield tissue samples large enough for accurate diagnosis. HRCT should be used to target areas of active disease and avoid lung regions with end-stage fibrosis, which is nondiagnostic.

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General Principles

Definition

ILDs are a heterogeneous group of >200 disorders characterized by infiltration of the lung interstitium by cells, fluid, and/or connective tissue.

ILDs can present acutely or chronically, and they are often diagnosed using a multidisciplinary approach employing pulmonary clinicians, radiologists, and pathologists.

Classification

  • ILDs can be broadly classified into those with known causes and those without (idiopathic).
    • Idiopathic interstitial pneumonias:1
      • Idiopathic pulmonary fibrosis (IPF) (idiopathic usual interstitial pneumonia [UIP])
      • Idiopathic nonspecific interstitial pneumonia (NSIP)
      • Desquamative interstitial pneumonia (DIP)
      • Respiratory bronchiolitis–associated interstitial lung disease (RB-ILD)
      • Cryptogenic organizing pneumonia (COP) (idiopathic OP)
      • Acute interstitial pneumonia (AIP)
      • Lymphoid interstitial pneumonia (LIP) (rare)
      • Idiopathic pleuroparenchymal fibroelastosis (rare)
    • Medication/therapy induced:
      • Bleomycin
      • Amiodarone
      • Nitrofurantoin
      • Checkpoint inhibitors
      • NSAIDs
      • Thalidomide
      • Rituximab
      • Azathioprine
      • Methotrexate
      • Radiation therapy
    • CTD-ILD:
      • Rheumatoid arthritis
      • Scleroderma
      • Sjögren syndrome
      • Antisynthetase syndrome
      • Mixed CTD
      • Systemic lupus erythematosus
    • Vasculitides:
      • Granulomatosis with polyangiitis
      • Eosinophilic granulomatosis with polyangiitis
      • Microscopic polyangiitis
      • Goodpasture syndrome
    • Pneumoconiosis (diseases of the lung due to dust inhalation):
      • Coal miners’ pneumoconiosis
      • Asbestosis
      • Silicosis
      • Siderosis
      • Stannosis
      • Mixed dust pneumoconiosis
    • Granulomatous ILD:
      • Sarcoidosis
      • Berylliosis
      • Hypersensitivity pneumonitis (HP)
      • Granulomatous–lymphocytic interstitial lung disease
      • Bronchocentric granulomatosis
    • Cystic lung diseases:
      • Lymphangioleiomyomatosis (LAM)
      • Pulmonary Langerhans cell histiocytosis (PLCH)
      • Birt–Hogg–Dubé (BHD) syndrome
      • Pulmonary amyloidosis
      • Light chain deposition disease
      • Postinfectious
    • Miscellaneous:
      • Erdheim–Chester disease
      • Pulmonary alveolar proteinosis
      • Lipoid pneumonia
      • Pulmonary alveolar microlithiasis
      • Acute eosinophilic pneumonia
      • Chronic eosinophilic pneumonia

Clinical Presentation

History

  • Obtaining a thorough history is of paramount importance in patients presenting with ILD and is often crucial in making a diagnosis.
  • Patients most often present with progressive dyspnea and persistent dry cough.
  • Duration of symptoms may help in differentiating ILDs. While many ILDs present with years of progressive dyspnea and cough, a subset of ILD patients present with acute or subacute onset of symptoms (AIP, acute eosinophilic pneumonia, OP), which may mimic infectious pneumonias with atypical organisms.
  • Past medical history is very important, not only for underlying diseases but also to identify ILDs related to disease management. Examples include CTDs and immunosuppressive agents; cancers along with chemo-, immuno-, and radiotherapies; and other systemic diseases that can potentially affect the lungs such as inflammatory bowel disease. It is important not to forget the use of over-the-counter medications.
  • Documenting a smoking history is essential. Some ILDs manifest almost exclusively in smokers (Langerhans cell histiocytosis, DIP, and RB-ILD). Some diseases are strongly associated with current or previous tobacco use, for example, IPF. Pulmonary hemorrhage is far more common in active smokers with Goodpasture disease than in prior or nonsmokers.
  • Exposures both at home and in the workplace should be evaluated. These may include exposures to radiation, asbestos, metal dusts, wood dusts, chemicals or fumes, pets, moldy environments, down comforters and/or pillows, and more. Patients should be questioned regarding the degree and duration of their exposures, and the use of respiratory protective equipment.
  • Family history should be obtained, specifically as it relates to pulmonary fibrosis, lung disease, or autoimmune disease. Multiple inheritance patterns have been described with ILDs including complex (sarcoidosis), autosomal dominant (tuberous sclerosis), and autosomal recessive (Hermansky–Pudlak syndrome).

Physical Examination

  • Extrapulmonary examination in patients with ILD should pay particular attention to findings of systemic diseases that may affect the lungs. These include CTDs, sarcoidosis, tuberous sclerosis, and others.
    • Examples include sclerodactyly, mechanic’s hands, Raynaud phenomenon, dry mucous membranes, telangiectasias, skin rashes, facial erythema, papules, eczema, or other skin lesions.
  • Cardiac examination should focus on findings suggesting the presence of PH/cor pulmonale including a right ventricular heave, pulmonary artery tap, tricuspid regurgitation holosystolic murmur, right-sided S3, and peripheral edema. These findings are usually indicative of advanced lung disease.
  • Clubbing is a very nonspecific finding described in lung diseases, heart diseases, and gastrointestinal (GI) diseases. It can be seen in IPF, sarcoidosis, PLCH, and other ILDs.
  • The pulmonary examination in ILDs is nonspecific. Findings may include dry inspiratory crackles, which are best noted posteriorly near the lung bases. Wheezes and inspiratory squeaks may also be noted.

Diagnostic Testing

Diagnostic testing in the evaluation of ILDs typically involves:

  • Chest imaging including CXR and high-resolution CT (HRCT) of the chest
  • Pulmonary function tests (PFTs)
  • Blood testing
  • Lung sampling including bronchoscopy and video-assisted thoracic surgery (VATS)

Chest Imaging

  • Review of old CXRs is often very helpful in assessing both the rate and extent of change of lung disease over time.
  • Up to 10% of CXRs may be normal in patients with ILD; as a result, a normal CXR may not exclude ILD in settings where the clinical suspicion of ILD is very high.
  • As a result of the wide variety of ILDs, CXRs may have a highly variable appearance.
  • The most common abnormality on CXR in ILD is a reticular pattern of linear opacities that may be localized or form a network involving the lungs diffusely.
  • However, nodular opacities, alveolar opacities, mixed alveolar opacities, and reticular opacities and occasionally cystic changes are also seen.
  • Extensive fibrosis of the lungs may lead to volume loss in one or both lungs.
  • Patients with known or suspected ILDs should undergo CT scanning as the diagnosis of many ILDs relies on HRCT.2
  • HRCT is a scanning technique that uses thin slice (usually 1-mm thick) images that are obtained and processed using a high-frequency reconstruction algorithm.2 Scans are obtained with the patient in a supine position during a breath hold at maximal inspiration and then during a breath hold at maximal expiration.
  • Prone imaging may be performed in cases where atelectasis obscures the posterior lung bases.
  • The pattern on HRCT is important in determining the differential diagnosis of ILD (Table 10-6). Notably, published guidelines exist for the definitive radiologic diagnosis of certain ILDs, specifically IPF.2
Table 10-6: Clinical and Radiologic Features of Interstitial Lung Diseases

Clinical FeaturesHRCT Findings
UIP
  • Insidious onset and progressive dyspnea
  • Dry cough
  • Poorly responsive to treatment, poor long-term survival
  • Variable course punctuated by intermittent exacerbations
  • Pattern can be associated with connective tissue disease
  • Older patients >50 y
  • Male predominance
  • UIP on CT or biopsy forms the radiologic basis for diagnosing IPF in the absence of underlying cause
  • Subpleural, basal predominant reticulation/interstitial thickening
  • Honeycombing with/without traction bronchiectasis
  • Heterogeneous (geographic) distribution
  • Absence of ground glass, consolidation, micronodules, cysts, or air trapping
  • May have atypical distribution in familial cases
NSIP
  • Associated with younger patients
  • More common in females
  • Commonly associated with collagen vascular diseases, including scleroderma, rheumatoid arthritis, and antisynthetase syndrome
  • Response to therapy is variable depending on etiology
  • Interstitial thickening, often with peripheral subpleural sparing
  • Ground-glass infiltrates
  • Traction bronchiectasis
  • Homogeneous distribution
  • In end-stage disease, may develop fibrotic changes and “bronchiolectasis” that resembles UIP
RB-ILD
  • Associated with cigarette smoking
  • Generally responsive to smoking cessation
  • Bronchiolocentric ground-glass nodules with an upper lobe predominance
DIP
  • Associated with cigarette smoking and occupational exposures
  • Generally responsive to smoking cessation
  • May be treated with corticosteroids
  • Peripheral ground-glass opacities or consolidation
  • May have small, well-defined cysts
COP
  • Subacute course, often presents as multiple outpatient treatment failures of bronchitis/pneumonia
  • Often associated with infections or drug exposures
  • Responsive to prolonged courses of corticosteroids
  • Often recurs if steroids are withdrawn too rapidly
  • Multifocal ground-glass opacities and consolidations
  • Usually lower lobe predominant
  • Infiltrates may be migratory on serial imaging
  • May have “reverse halo” or atoll sign
Sarcoidosis
  • Dyspnea, cough, and chest pain are common presenting symptoms
  • Systemic symptoms may be prominent
  • Approximately 1 in 20 cases are asymptomatic and incidentally detected on CXR
  • Almost any organ system may be affected
  • Perilymphatic nodules
  • Patchy ground-glass opacities
  • Reticular infiltrates
  • Traction bronchiectasis
  • Progressive massive fibrosis
  • Hilar or mediastinal lymphadenopathy
Fibrotic HP/fibrotic HP with honeycombing
  • Presents in a similar fashion to UIP/IPF
  • There may be a history of systemic symptoms (fever, myalgias)
  • Associated with environmental exposures (birds, molds, hot tubs) but these are identified in <50% of cases
  • Reticular abnormality with an upper or mid-lung predominance
  • Micronodules
  • Mosaic attenuation/air trapping
  • Peribronchovascular predominance
  • Honeycombing may be present in more advanced disease

BAL, bronchoalveolar lavage; COP, cryptogenic organizing pneumonia; DIP, desquamative interstitial pneumonia; HP, hypersensitivity pneumonitis; HRCT, high-resolution CT; ILD, interstitial lung disease; IPF, idiopathic pulmonary fibrosis; NSIP, nonspecific interstitial pneumonia; RB-ILD, respiratory bronchiolitis–associated interstitial lung disease; UIP, usual interstitial pneumonia.

Data from Kadoch MA, Cham MD, Beasley MB, et al. Idiopathic interstitial pneumonias: a radiology-pathology correlation based on the revised 2013 American Thoracic Society-European Respiratory Society classification system. Curr Probl Diagn Radiol. 2015;44:15-25  [PMID:25512168]; Raghu G, Collard HR, Egan JJ, et al. An official ATS/ERS/JRS/ALAT statement: idiopathic pulmonary fibrosis – evidence-based guidelines for diagnosis and management. Am J Respir Crit Care Med. 2011;183:788-824  [PMID:21471066]; Webb RW, Higgins CB. Thoracic Imaging: Pulmonary and Cardiovascular Radiology. Lippincott Williams & Wilkins; 2005.

Pulmonary Function Testing

  • PFTs are a noninvasive set of tests that allow for evaluation of lung function, stratification of disease severity, and for monitoring of disease progression over time.
  • Complete pulmonary function testing involves spirometry, lung volumes, and diffusing capacity (DLCO), along with resting and exercise pulse oximetry.
  • PFTs allow us to determine whether patients have restrictive lung disease, obstructive lung disease, or a mixed pattern of disease. This aids in the differential diagnosis of ILD.
  • While most fibrotic ILDs demonstrate a restrictive pattern on PFTs, a number of ILDs may demonstrate obstruction, including smoking-related lung diseases (RB-ILD and PLCH), cystic lung diseases (LAM and BHD), and sarcoidosis.
  • DLCO is commonly decreased in patients with ILD but is a nonspecific finding.
  • In some cases, the presence of coexisting COPD in patients with ILDs may lead to a mixed pattern of lung disease on PFTs. In other cases, pseudonormalization of PFTs occurs where the combination of restriction and obstruction leads to the finding of “normal” testing. In these cases, a low DLCO may be the only clue that the patient has significant underlying lung disease when the PFTs are reviewed in isolation.
  • Resting and exercise pulse oximetry are commonly assessed using a 6MW test.
  • Serial PFTs obtained at follow-up visits are a useful way to monitor for disease progression and may have prognostic significance.3

Laboratories

  • Routine laboratory testing in the evaluation of ILD patients includes CBC, BMP, and LFT testing. These may provide clues to the diagnosis (eosinophilia).
  • Many drugs used in the treatment of ILD require regular monitoring of blood counts, renal function, or liver function.
  • Serologic testing for CTDs is obtained in all patients with clinical stigmata of CTD.
  • Aldolase and creatinine kinase may be tested to evaluate for evidence of myositis in patients with a clinical suspicion for antisynthetase syndrome. In cases where suspicion is high for myositis, panels of muscle-specific antibodies should also be obtained.
  • In any patient with a high suspicion for scleroderma or Sjögren disease, an ENA panel should be obtained. ENA panels vary but contain a wide variety of antibodies to screen for CTD.
  • In practice, serologic testing is often obtained in a wide range of patients to exclude subclinical CTD. Many centers obtain a minimum of an antinuclear antibody (ANA), rheumatoid factor, and a cyclic citrullinated peptide antibody tests, even patients with suspected IPF, since rheumatoid arthritis ILD often presents with a UIP pattern on HRCT.
  • In patients with cystic lung disease on imaging, testing for vascular endothelial growth factor type D (VEGF-D) may be helpful in making the diagnosis of LAM. Levels of VEGF-D > 800 pg/mL in the correct clinical or radiographic setting can be diagnostic of LAM.4
  • Genetic testing can also be helpful in cystic lung diseases and can screen for tuberous sclerosis–associated LAM (TSC1 and TSC2 gene mutations) and BHD (FLCN, folliculin gene mutations) where appropriate.

Lung Sampling

  • When an extensive evaluation does not result in a confident diagnosis, lung sampling can be considered.
  • Bronchoalveolar lavage (BAL) is used to sample the cellular content of the lungs. It has limited utility in the evaluation of ILD.
  • BAL is useful in excluding coexisting infection and, in some cases, malignancy. It is also useful in cases where diffuse alveolar hemorrhage or eosinophilic lung disease is suspected.5
  • Lung biopsy should only be undertaken at centers with expertise in evaluating ILD patients. Generally, biopsy should be reserved for circumstances where the diagnosis is uncertain and clarification would result in a significantly altered approach to management.
  • While lung biopsy is desired in many cases, patients with ILD are often considerably physiologically impaired and may not tolerate the procedure.
  • Although many patients tolerate lung biopsy well, certain subgroups of patients are predisposed to complications, including decompensation of their ILD following lung biopsy.6 Patients with IPF may develop disease exacerbations following lung biopsy, resulting in disease progression and even death.
  • Two types of lung biopsy are available: transbronchial forceps biopsy (TBBx) and VATS biopsy.
  • TBBx is often performed along with BAL during bronchoscopy. It is most useful in cases in which small biopsy samples suffice for diagnosis.
  • TBBx has the highest yield in bronchiolocentric ILDs, such as sarcoidosis, berylliosis, and lymphangitic carcinomatosis.7 It is also useful in cases where eosinophilic pneumonia or pulmonary alveolar proteinosis is suspected.
  • TBBx is insufficient for differentiating most idiopathic ILDs, especially between UIP and NSIP, given inadequate sample size.
  • However, a recently developed test, the Envisia Genomic Classifier, uses genomic patterns in TBBx samples to distinguish UIP fibrotic lung disease from non-UIP fibrotic lung disease. It is may helpful in well-selected patients with lung fibrosis who would not tolerate VATS biopsy.
  • Transbronchial cryobiopsy is a newer option that allows for larger volume tissue sampling without a surgical lung biopsy. Further studies are required to integrate this technique into the ILD diagnostic algorithm.8
  • In cases with UIP patterns, VATS biopsies are preferred as they yield tissue samples large enough for accurate diagnosis. HRCT should be used to target areas of active disease and avoid lung regions with end-stage fibrosis, which is nondiagnostic.

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