Interstitial Lung Diseases

Interstitial lung diseases (ILDs) are a varied group of disorders characterized by impairment in lung function and gas exchange due to the accumulation of extracellular matrix proteins in the parenchyma of the lungs.  Known causes of ILD include connective tissue or systemic autoimmune rheumatic diseases, genetic abnormalities, pneumotoxic medications or treatments, infections, occupational exposure to materials such as asbestos, and smoking    but in many cases, the cause of ILD is unknown. 

Distinguishing between ILD types can be challenging, but differentiation is important for appropriate disease management and prognosis, particularly because treatment is based on the probable etiology of the disease.    Diagnosis depends on clinical examination, a thorough patient history, laboratory testing, imaging, and in some cases, bronchoalveolar lavage analysis and/or tissue biopsy.   Laboratory tests in the workup of ILD include nonspecific tests such as calcium, creatinine, liver function, and muscle enzyme tests, as well as autoantibody testing.  A full serologic workup to detect autoimmune antibodies associated with connective tissue diseases is recommended. 

Quick Answers for Clinicians

What are the types of interstitial lung diseases?

More than 100 types of interstitial lung disease (ILD) have been identified.  The diseases can be grouped into six main categories: connective tissue disease related, smoking related, occupation related, medication induced, hypersensitivity pneumonitis, or idiopathic pulmonary fibrosis.  Some other less common types of ILD exist as well (eg, graft-versus-host disease).  The connective tissue diseases most frequently associated with ILD include systemic sclerosis, rheumatoid arthritis, Sjögren syndrome, systemic lupus erythematosus, mixed connective tissue diseasesystemic vasculitis, and inflammatory myopathies such as polymyositis (an antisynthetase syndrome) and dermatomyositis. Visit the individual ARUP Consult topics for more specific information about laboratory testing for these diseases.

In the case of connective tissue disease-associated interstitial lung disease, does the connective tissue disease always manifest first?

In some patients, interstitial lung disease (ILD) may be the first manifestation of a connective tissue disease.  Workup of the ILD should include a thorough autoimmune evaluation (ie, serologic testing) to identify an associated connective tissue disease.  Panel tests that detect a variety of autoantibodies are the most efficient testing approach. 

How are serologic laboratory tests helpful in distinguishing between interstitial lung disease types?

In combination with other clinical findings, serologic testing can help narrow the diagnosis to a particular type of interstitial lung disease (ILD). For example, increased antibodies against Sjögren syndrome-related antigen A (SS-A) and Sjögren syndrome-related antigen B (SS-B) suggest Sjögren syndrome-associated ILD.  Increased cytoplasmic antineutrophil cytoplasmic antibodies (c-ANCAs) may point to ILD related to granulomatosis with polyangiitis, and increased anti-Jo-1 or other antisynthetase autoantibodies suggest ILD associated with polymyositis or dermatomyositis.  Serologic testing may be particularly helpful in diagnosing antisynthetase syndrome in patients with connective tissue disease-related ILD. This syndrome can present a diagnostic challenge because patients may not have obvious signs of systemic disease or strong evidence of myositis. 

Indications for Testing

Testing for ILD is appropriate in individuals with symptoms of ILD and:

Asymptomatic family members of those with an ILD-associated gene variant may warrant testing and counseling (see Genetic Testing).

Laboratory Testing

Diagnosis

Nonspecific Testing

Nonspecific laboratory tests in the workup of ILDs include CBC, creatinine, calcium, urine (to detect abnormal sediment), liver function, muscle enzyme, and lymphocyte proliferation tests.  Serum markers, such as erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP), are useful for the detection of systemic inflammation.  Abnormal results, in the context of other clinical information such as patient history, examination, and imaging, can help narrow the diagnosis to a particular form of ILD.  For example, detection of eosinophilia on a CBC can suggest drug toxicity or eosinophilic pneumonia, whereas normocytic anemia can point to connective tissue disease or chronic disease. 

Biomarkers for Lung-Specific Injury and Inflammation

Additional serum markers, such as surfactant protein D (SP-D) and Krebs von den Lungen-6 (KL-6), may be helpful to assess lung damage in patients with ILD.   SP-D is involved in pulmonary immune response, and serum levels of SP-D serve as a marker of disease activity in ILD.  SP-D levels may also be useful for disease monitoring.  See Monitoring below.

Patients with ILD have higher KL-6 levels compared with patients with other pulmonary illnesses and healthy individuals, and increased KL-6 levels in serum serve as a marker for lung damage.  KL-6 testing is considered to have a role in ILD diagnosis and determination of disease severity, and may be useful for disease monitoring.  See Monitoring below.

Autoimmune Serologic Testing

A full serologic workup to detect antibodies associated with specific connective tissue diseases is recommended in all patients with ILD.  The particular tests are determined in part by clinical presentation and context, but may include the autoantibodies listed in the table below. Use of a panel test that detects a variety of autoantibodies may be the most efficient testing approach.​

Autoantibody Testing to Consider in Patients with Suspected ILDa
ANCAs (ANCA-associated vasculitis) c-ANCA, p-ANCA, anti-MPO, anti-PR3
Rheumatoid arthritis-associated antibodies anti-CCP, RF
Systemic sclerosis-associated antibodies anti-Scl-70, anticentromere, anti-RNA polymerase III
SLE-associated, mixed connective tissue disease-associated, or Sjögren syndrome-associated antibodies ANAs, anti-dsDNA, anti-SSA-52 (Ro52), SSA-60 (Ro60), anti-SS-B, anti-Smith, Sm/RNP
Myositis-specific and myositis-associated antibodies anti-Jo1, anti-PL-7, anti-PL-12, anti-EJ, anti-OJ, anti-SRP, anti-MDA5, NXP-2, anti-Ku, PM/Scl-100, Sm/RNP, SSA-52
aRefer to ARUP Laboratories’ Interstitial Lung Disease Autoantibody Panel 3001784.

ANAs, antinuclear antibodies; ANCAs, antineutrophil cytoplasmic antibodies; c-ANCA, cytoplasmic antineutrophil cytoplasmic antibody; CCP, cyclic citrullinated peptide; dsDNA, double-stranded DNA; MPO, myeloperoxidase; p-ANCA, perinuclear antineutrophil cytoplasmic antibody; PR3, proteinase 3; RF, rheumatoid factor; RNP, ribonucleoprotein; SS-A, Sjögren’s syndrome-related antigen A; SS-B, Sjögren’s syndrome-related antigen B; SRP, signal recognition particle; SLE, systemic lupus erythematosus​

Sources: Kalchiem-Dekel, 2018 ; Arulkumaran, 2011 

Visit the Connective Tissue Disease ARUP Consult topic for additional information about ANA testing (including a comparison of ANA testing methods) in connective tissue/systemic autoimmune rheumatic diseases.

Visit individual ARUP Consult topics for more information about the use of laboratory testing for specific ILD-associated connective tissue diseases:

Hypersensitivity Pneumonitis Testing (for Exposure-Related Interstitial Lung Disease)

Hypersensitivity pneumonitis, also called extrinsic allergic alveolitis, is one of the subgroups of ILD and typically results from exposure to organic antigens in the environment, such as mold, farming-related antigens, and avian proteins.  In cases of suspected hypersensitivity pneumonitis, testing for antigens such as Aspergillus flavus, A. fumigatus, Aureobasidium pullulans, Micropolyspora faeni, Saccharomonospora viridis, Thermoactinomyces candidus, T. vulgaris, and pigeon serum is recommended. See ARUP Lab Tests below for disease-specific tests, and the Hypersensitivity Pneumonitis ARUP Consult topic for additional information about this disease.

Genetic Testing

Some forms of ILD are associated with genetic conditions such as Hermansky-Pudlak syndrome, and a number of variants have been linked to an increased risk of ILD disorders (eg, chronic beryllium disease and sarcoidosis).  Genetic variants are also risk factors in both sporadic and familial idiopathic pulmonary fibrosis, and have prognostic relevance. 

Genetic testing should be considered in all patients who have ILD and a family history of ILD.  Some investigators recommend that personal and family history be evaluated, in conjunction with biomarkers, to identify families likely to have a genetic diagnosis before proceeding with genetic testing.  The detection of a variant associated with a familial form of ILD warrants consideration of genetic testing and counseling in asymptomatic family members who may be at risk. 

Monitoring

Monitoring of ILDs primarily involves lung function testing, evaluation of dyspnea, and imaging.  In addition, both KL-6 and SP-D may be helpful in monitoring patients with an established diagnosis of ILD because both markers increase with disease exacerbation and decrease when treatment results in disease improvement.   These markers may also be useful to identify disease progression. 

ARUP Laboratory Tests

Autoimmune Serologic Tests

May be useful for evaluation of ILD in the context of connective tissue disease

Components: Ro52, Ro60, Jo-1, PL-7, PL-12, EJ, Ku, SRP, OJ, PM/Scl-100, MDA5, CCP, Scl-70, RA, ANA, NXP-2 antibodies

Serum Marker Tests

Preferred initial panel for the evaluation of lung inflammation or injury in various types of ILD

Components: KL-6, SP-D

May aid in the evaluation of lung inflammation or injury in various types of ILD

Hypersensitivity Pneumonitis Tests (for Exposure-Related ILD)

Evaluate patients suspected of having hypersensitivity pneumonitis induced by exposure to Aspergillus fumigatus, Aurebasidium pullulans, Micropolyspora faeni, Thermoactinomyces vulgaris, or pigeon serum

Evaluate patients suspected of having hypersensitivity pneumonitis induced by exposure to Aspergillus flavus, Aspergillus fumigatus, Saccharomonospora viridis, and Thermoactinomyces candidus

Evaluate patients suspected of having hypersensitivity pneumonitis induced by exposure to Aspergillus flavus, Aspergillus fumigatus, Aureobasidium pullulans, Micropolyspora faeni, Saccharomonospora viridis, Thermoactinomyces candidus, Thermoactinomyces vulgaris, or pigeon serum

Evaluate patients suspected of having hypersensitivity pneumonitis induced by exposure to Aspergillus flavus, Aspergillus fumigatus, Aurebasidium pullulans, Micropolyspora faeni, Saccharomonospora viridis, Thermoactinomyces candidus, Thermoactinomyces vulgaris, or pigeon serum

Testing also includes the following allergens: Feather Mix, Beef, Pork, and Phoma betae

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