Interstitial Lung Diseases

Indications for Testing

Laboratory testing in patients with ILD can be useful to determine etiology and monitor disease course. Etiologic factors associated with ILD that indicate a need for testing include:

• Underlying autoimmune diseases (e.g., CTD or systemic autoimmune rheumatic disease)
• Environmental and occupational exposures (e.g., silica dust, asbestos, fungal antigens, avian antigens)
• Drug-induced, radiation-induced, or postinfectious lung injury
• Genetic predispositions (i.e., known gene variants associated with the risk of developing ILD); refer to Genetic Testing for more information

Surveillance

Current guidelines emphasize chest computed tomography (CT) scanning as the primary method for detecting interstitial lung abnormalities (ILAs) and early ILD in at‑risk groups (e.g., individuals with high‑risk CTDs or a family history of pulmonary fibrosis). Lab testing is not used for routine surveillance for ILD, but serologic evaluation may be recommended when ILAs are detected to assess for underlying CTDs. Genetic testing (e.g., MUC5B promoter variant testing) is not advised for surveillance. 

Laboratory Testing

Diagnosis

Laboratory tests in the workup of ILDs may include a CBC, hepatic function tests, renal function tests, serologic tests, serum or plasma markers, and, in some cases, tests for infectious diseases. [Antoine 2023 -2] 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, and detection of hemolytic anemia can suggest systemic lupus erythematosus (SLE).  Serum markers such as erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) are useful for the detection of systemic inflammation. 

Biomarkers for Lung-Specific Injury and Inflammation

The use of lung-specific markers for the evaluation and monitoring of ILDs has been studied as an alternative to imaging and pulmonary function tests. Serum concentrations of Krebs von den Lungen-6 (KL-6) and surfactant protein D (SP-D) are significantly elevated in patients with ILD compared to those without ILD, indicating the diagnostic utility of these biomarker concentrations.  KL-6 and SP-D concentrations have also been correlated with lung injury and disease severity, which suggests their potential utility for prognosis and monitoring. 

Autoimmune Serologic Testing

Serologic testing to detect autoimmune antibodies can help identify specific CTDs as the underlying cause of ILDs. Test selection is based in part on clinical presentation and context, but tests may include the autoantibodies listed in the following table. Use of a panel test that detects a variety of autoantibodies may be the most efficient testing approach.

Visit the ARUP Consult Connective Tissue Diseases - Systemic Autoimmune Rheumatic Diseases topic for additional information about ANA testing (including a comparison of ANA testing methods) in these diseases.

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

• Sjögren syndrome
• Systemic sclerosis
• Systemic lupus erythematosus
• Rheumatoid arthritis
• Mixed connective tissue disease
• Inflammatory myopathies (e.g., antisynthetase syndrome and dermatomyositis)

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

Hypersensitivity pneumonitis, historically referred to as 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 antibodies against antigens such as Aspergillus flavus, Aspergillus fumigatus, Aureobasidium pullulans, Micropolyspora faeni, Saccharomonospora viridis, Thermoactinomyces candidus, Thermoactinomyces vulgaris, and pigeon serum is recommended. 

Genetic Testing

ILDs can be hereditary, and family history is the strongest risk factor for idiopathic forms.  Familial ILDs often present with an autosomal dominant pattern of inheritance with incomplete penetrance, which means that affected individuals typically appear in each successive generation but may demonstrate variability in symptom severity and/or onset.  However, cases of autosomal recessive and X-linked inheritance have also been documented. 

Studies of familial ILD cases have identified associations with surfactant-related genes (SRGs), such as SFTPC, and telomere-related genes (TRGs), including TERT and TERC. 

Some forms of ILD are associated with genetic conditions such as Hermansky-Pudlak syndrome (caused by pathogenic variants in multiple genes), brain-lung-thyroid syndrome (caused by pathogenic variants in the NKX2-1 gene), and COPA syndrome (caused by pathogenic variants in the COPA gene). 

Genetic testing should be considered in patients with ILD and a family history suggestive of a genetic etiology. Evaluating personal and family history, along with relevant biomarkers, may help identify individuals most likely to benefit from testing. Although most patients will not have an identifiable genetic cause, a negative genetic test does not rule out a genetic contribution. If a pathogenic variant associated with familial ILD is detected, genetic testing and counseling should be offered to at-risk relatives. 

Pediatric Genetic Testing Recommendations

Specific guidelines exist for the evaluation of pediatric ILD.  Individuals younger than 2 years may be classified as having “chILD syndrome” if they present with diffuse lung disease without known cause and meet certain clinical criteria. 

Monitoring

Monitoring of ILDs primarily involves pulmonary function testing, evaluation of dyspnea, and imaging.  Serum concentrations of KL-6 and SP-D have been correlated with disease severity and may be useful in monitoring disease progression.