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Approach to the adult with interstitial lung disease: Diagnostic testing

Approach to the adult with interstitial lung disease: Diagnostic testing
Literature review current through: Jan 2024.
This topic last updated: Feb 27, 2023.

INTRODUCTION — The diffuse parenchymal lung diseases (DPLD), often collectively referred to as the interstitial lung diseases (ILDs), are a heterogeneous group of disorders that are classified together because of similar clinical, radiographic, physiologic, or pathologic manifestations (algorithm 1) [1-5]. The descriptive term "interstitial" reflects the pathologic appearance that the abnormality begins in the interstitium, but the term is somewhat misleading, as most of these disorders are also associated with extensive alteration of alveolar and airway architecture.

The initial evaluation of patients with ILD is aimed at identifying the etiology of the ILD and its severity. The results of laboratory, radiographic, and pulmonary function tests guide the decisions about whether to pursue bronchoalveolar lavage and/or transbronchoscopic, thoracoscopic, or open lung biopsy.

An overview of the diagnostic testing that is helpful in the diagnosis of ILD will be presented here (algorithm 2) [6-8]. The clinical findings that aid in the diagnosis of ILD and the individual causes of ILD are discussed separately. (See "Approach to the adult with interstitial lung disease: Clinical evaluation" and "Idiopathic interstitial pneumonias: Classification and pathology" and "Clinical manifestations and diagnosis of sarcoidosis" and "Role of bronchoalveolar lavage in diagnosis of interstitial lung disease" and "Pulmonary toxicity associated with systemic antineoplastic therapy: Clinical presentation, diagnosis, and treatment".)

CAUSES OF ILD — The list of causes of ILD, also known as diffuse parenchymal lung disease, is broad and includes those ILDs that are associated with a broad range of diseases (table 1), exposures (table 2A-B), and drugs (table 3). ILD may also occur as an idiopathic condition (algorithm 1 and table 4). The treatment choices and prognosis vary among the different causes and types of ILD, so ascertaining the correct diagnosis is important.

A variety of infectious processes cause interstitial opacities on chest radiograph, including fungal pneumonias (eg, coccidioidomycosis, cryptococcosis, Pneumocystis jirovecii), atypical bacterial pneumonias, and viral pneumonias. These infections often occur in immunocompromised hosts and are discussed separately. (See "Approach to the immunocompromised patient with fever and pulmonary infiltrates".)

The most common identifiable causes of ILD are exposure to occupational and environmental agents (table 2A-B), especially to inorganic or organic dusts, and drug-induced pulmonary toxicity (table 3). (See "Asbestos-related pleuropulmonary disease" and "Chronic beryllium disease (berylliosis)" and "Silicosis" and "Hypersensitivity pneumonitis (extrinsic allergic alveolitis): Clinical manifestations and diagnosis".)

ILD can potentially complicate the course of most of the rheumatic diseases (eg, polymyositis/dermatomyositis, rheumatoid arthritis, systemic lupus erythematosus, systemic sclerosis [scleroderma], mixed connective tissue disease).

Idiopathic causes of ILD include sarcoidosis, cryptogenic organizing pneumonia, acute and chronic eosinophilic pneumonia, and the idiopathic interstitial pneumonias (algorithm 1). The idiopathic interstitial pneumonias have been further characterized: idiopathic pulmonary fibrosis (usual interstitial pneumonia), desquamative interstitial pneumonia, respiratory bronchiolitis-interstitial lung disease, acute interstitial pneumonia, and nonspecific interstitial pneumonia. (See "Idiopathic interstitial pneumonias: Classification and pathology".)

CLINICAL EVALUATION — The initial recognition that a patient may have an interstitial lung disease (ILD) usually follows the onset of progressive breathlessness with exertion (dyspnea), a persistent nonproductive cough, and/or pulmonary symptoms associated with another disease, such as a rheumatic disease. The clinical evaluation includes careful exploration of past medical history (comorbidities, medications, irradiation), potential exposures (occupational, avocational, environmental, infectious), and extrapulmonary evidence of a systemic illness. The clinical evaluation of ILD is discussed separately. (See "Approach to the adult with interstitial lung disease: Clinical evaluation".)

Laboratory tests — The routine laboratory evaluation of suspected ILD typically includes biochemical tests to evaluate hepatic and renal function; hematologic tests with differential blood count to check for evidence of anemia, polycythemia, leukocytosis, or eosinophilia; and urinalysis (table 5) [1]. Depending on the clinical situation and results of hepatic function tests, hepatitis serology and HIV testing may be appropriate.

Serologic studies – Serologic studies are obtained to ensure that subclinical rheumatic disease is not overlooked. We typically obtain anti-nuclear antibodies (ANA), rheumatoid factor, and cyclic citrullinated peptide antibodies [2]. We reserve additional testing with other serological studies, for example, antisynthetase antibodies (eg, Jo-1), creatine kinase and aldolase, Sjögren’s antibodies (SS-A, SS-B), scleroderma antibodies (anti-topoisomerase [Scl-70]), antimelanoma differentiation-associated gene 5 (anti-MDA-5), and overlap antibodies (PM-1, also known as PM-Scl), for patients with a clinical suspicion of rheumatic disease (table 5). However, not all patients with positive serologic tests will develop a well-differentiated rheumatic disease [9-11].

Importantly, patients should be carefully screened for signs and symptoms of rheumatic disease, as ILD precedes the onset of myositis in about 70 percent of patients with the anti-synthetase syndrome, and the ANA may be negative [3]. (See "Interstitial lung disease in dermatomyositis and polymyositis: Clinical manifestations and diagnosis", section on 'Clinical features' and "Clinical manifestations and diagnosis of systemic sclerosis (scleroderma) in adults", section on 'Evaluation for suspected systemic sclerosis'.)

Serologic testing for hypersensitivity pneumonitis antibodies is based on patient exposure to potential antigens. (See "Hypersensitivity pneumonitis (extrinsic allergic alveolitis): Clinical manifestations and diagnosis", section on 'Laboratory tests'.)

Further evaluation of positive ANA – For patients with a positive ANA, further evaluation may include anti-double-stranded DNA, a myositis panel (anti-synthetase antibodies [including anti-Jo-1], anti-Ro/SSA, anti-PM/Scl), anti-Sm, and anti-U1 ribonucleoprotein (U1 RNP; previously called antibody to extractable nuclear antigen) to further evaluate for systemic lupus erythematosus and mixed connective tissue disease. (See "Measurement and clinical significance of antinuclear antibodies" and "Antibodies to double-stranded (ds)DNA, Sm, and U1 RNP".)

ILD and pulmonary hemorrhage – For patients presenting with pulmonary hemorrhage, we typically test for antiglomerular basement membrane antibodies, antineutrophil cytoplasmic antibodies (ANCA), antinuclear antibodies (ANA), antiphospholipid antibodies, and antistreptococcal antibodies. (See "The diffuse alveolar hemorrhage syndromes", section on 'Clues to a specific etiology'.)

Tests that are unlikely to be helpful diagnostically – We generally do not find it helpful diagnostically to obtain a C-reactive protein level or a sedimentation rate, as these are entirely nonspecific. Hypergammaglobulinemia is commonly observed in patients with ILD but is also nondiagnostic. (See "Acute phase reactants".)

Serum angiotensin converting enzyme (ACE) levels are generally not helpful in the initial evaluation of ILD, because of the low sensitivity and specificity of the test for sarcoidosis. (See "Clinical manifestations and diagnosis of sarcoidosis", section on 'Proposed activity tests, including angiotensin converting enzyme (ACE) level'.)

Biomarkers for research use – A number of serum markers suggestive of ILD have been identified, including surfactant protein A and B (SP-A, SP-B), monocyte chemoattractant protein-1 (MCP-1), and Kerbs von Lungren (KL)-6, a circulating, high-molecular weight glycoprotein expressed by type II pneumocytes [4,6,7,12,13]. In one report, the receiver operating characteristics of these four markers were evaluated in a mixed population of patients with idiopathic ILD, collagen vascular disease-associated ILD, and controls with and without pulmonary disease [6]. KL-6 was associated with the highest sensitivity, specificity, and diagnostic accuracy for the presence of ILD (94, 96, and 94 percent, respectively). The clinical role of these serum markers in the diagnosis of ILD is unclear and these tests are generally not commercially available.

In the future, the KL-6 assay may help to identify and monitor ILD in patients with rheumatoid arthritis and other rheumatic diseases. (See "Interstitial lung disease in rheumatoid arthritis".)

IMAGING

Chest radiography — The most common radiographic abnormality on routine chest radiograph is a reticular pattern (image 1); however, nodular (image 2) or mixed patterns (alveolar filling and increased interstitial markings) are not unusual (table 6A-C) [8]. Although the chest radiograph is useful in suggesting the presence of ILD, the correlation between the radiographic pattern and the stage of disease (clinical or histopathologic) is generally poor. Only the radiographic finding of honeycombing (small cystic spaces) correlates with pathologic findings and, when present, portends a poor prognosis.

In the evaluation of ILD, it is important to review all previous chest films to assess the rate of change in disease activity.

The chest radiograph is normal in as many as 10 percent of patients with some forms of ILD, particularly those with hypersensitivity pneumonitis. Thus, a complete evaluation should be undertaken even if a symptomatic patient has a normal chest radiograph or an asymptomatic patient has radiographic evidence of ILD. Failure to adequately evaluate such individuals may lead to disease progression that is irreversible by the time the patient seeks additional medical attention. The radiologic patterns and disease distributions associated with specific ILDs are discussed separately. (See "Evaluation of diffuse lung disease by conventional chest radiography".)

Computed tomography — The diagnostic approach to ILD relies on high-resolution computed tomography (HRCT) of the chest [14,15]. Image acquisition should be tailored for ILD evaluation, which differs from conventional chest computed tomography (CT) protocols. The scanner hardware, however, is standard and available at most sites. Intravenous contrast is usually not administered for HRCT image acquisition. However, if pulmonary embolism is a diagnostic consideration in a patient with acutely worsening symptoms, computed tomography pulmonary angiography (CTPA) should be obtained as an initial study or in combination with HRCT and will require intravenous contrast administration. (See "Clinical presentation, evaluation, and diagnosis of the nonpregnant adult with suspected acute pulmonary embolism", section on 'Computed tomography pulmonary angiography'.)

HRCT for ILD involves volumetric, rather than sequential, imaging with ≤1.5 mm slice thickness. Images of the entire chest are obtained with the patient in the supine position at sustained end-inspiration and then at sustained end-expiration [14,16]. Prone inspiratory imaging is sometimes performed, if there is uncertainty about dependent atelectasis.

Low radiation dose techniques, if available, are used. The effective radiation dose of a chest CT is approximately 7 mSv using standard techniques and 2 mSv using low-dose techniques; these are comparable to natural background radiation for two years and seven months, respectively.

HRCT findings help to narrow the differential diagnosis of ILD. The correlations between the various HRCT patterns and likely diagnoses are shown in the table (table 7A-B) [5,17-19] (see "High resolution computed tomography of the lungs"). As examples:

Bilateral symmetric hilar adenopathy and upper lung zone reticular opacities suggest sarcoidosis or another granulomatous disease.

Pleural plaques with linear calcification in association with a basilar predominance of reticular opacities suggest asbestosis. (See "Asbestos-related pleuropulmonary disease".)

Centrilobular nodules that spare the subpleural region are seen in hypersensitivity pneumonitis, sarcoidosis, Langerhans cell histiocytosis and also respiratory, follicular, and cellular bronchiolitis.

Irregular cysts associated with nodules in the upper and middle lung zones suggest pulmonary Langerhans cell histiocytosis. (See "Pulmonary Langerhans cell histiocytosis".)

Reticular opacities, traction bronchiectasis, and honeycombing (clustered airspaces 3 to 10 mm in diameter) in a predominantly subpleural and basal distribution are the imaging features associated with a histopathologic pattern of usual interstitial pneumonitis (UIP) (algorithm 1) [20,21]. While ground glass opacities may be present, they should be superimposed on reticular opacities to be considered indicative of UIP [14]. A UIP pattern is seen in idiopathic pulmonary fibrosis, chronic hypersensitivity pneumonitis, and ILD-associated with rheumatic diseases, such as rheumatoid arthritis and systemic sclerosis.

In an asymptomatic patient, diffuse, calcified, nodular, interstitial opacities may reflect healed varicella-zoster pneumonia [22].

Other imaging — Other types of chest imaging, such as (18)F-2-deoxy-2-fluoro-D-glucose (FDG) positron emission tomography (PET) scans, are rarely useful in the evaluation of ILD.

FDG-PET scanning – We do not typically obtain FDG-PET scans in the evaluation of ILD, as the findings are nonspecific. In a series of 35 patients with pulmonary lymphangitic carcinomatosis, diffuse uptake of FDG was noted in 30 patients and focal uptake in four [23]. However, FDG-PET positivity does not differentiate malignant from benign ILD, as FDG uptake can also be seen in sarcoidosis and pulmonary Langerhans cell histiocytosis. (See "Pulmonary Langerhans cell histiocytosis", section on 'Imaging' and "Clinical manifestations and diagnosis of sarcoidosis", section on 'Less commonly needed imaging'.)

PULMONARY FUNCTION TESTING — Complete lung function testing (spirometry, lung volumes, diffusing capacity) and resting and exercise pulse oximetry are obtained in virtually all patients with suspected ILD [1,24,25]. Measurement of lung function is most helpful for assessing the severity of respiratory impairment and the pattern, whether obstructive, restrictive, or mixed. The pattern is useful in narrowing the number of possible diagnoses.

Arterial blood gases are often obtained to corroborate results of pulse oximetry. (See "Overview of pulmonary function testing in adults" and "Office spirometry".)

Spirometry and lung volumes — Most of the interstitial disorders have a restrictive defect with reductions in total lung capacity (TLC), functional residual capacity (FRC), and residual volume (RV) [26,27]. Forced vital capacity (FVC) and forced expiratory volume in one second (FEV1) are decreased, but usually the changes are in proportion to the decreased lung volumes; thus, the FEV1/FVC ratio is usually normal or increased (figure 1). The reductions in lung volumes become more pronounced as lung stiffness increases with disease progression (figure 2). (See "Overview of pulmonary function testing in adults", section on 'Restrictive ventilatory defect'.)

In contrast, an interstitial pattern on chest radiograph accompanied by obstructive airflow limitation (ie, a reduced FEV1/FVC ratio) on lung function testing is suggestive of any of the following processes:

Sarcoidosis

Lymphangioleiomyomatosis (with or without tuberous sclerosis)

Hypersensitivity pneumonitis

Pulmonary Langerhans cell histiocytosis

Combined pulmonary fibrosis and emphysema

Constrictive bronchiolitis

Diffusing capacity — A reduction in the diffusing capacity (DLCO) is a common, but nonspecific finding in ILD. The decrease in DLCO is due, in part, to effacement of the alveolar capillary units but more importantly to the extent of mismatching of ventilation and perfusion of the alveoli. In some ILDs, particularly sarcoidosis, there can be considerable reduction in lung volumes and/or severe hypoxemia but normal or only slightly reduced DLCO. (See "Diffusing capacity for carbon monoxide".)

Moderate to severe reduction of DLCO in the presence of normal lung volumes in a patient with ILD suggests one of the following:

Combined emphysema and ILD

Combined ILD and pulmonary vascular disease

Pulmonary Langerhans cell histiocytosis

Pulmonary lymphangioleiomyomatosis

Pulmonary vascular disease, and thus a reduction in DLCO, can develop in patients with ILD as a consequence of hypoxemic vasoconstriction, thromboembolic disease complicating the ILD, or a disease with both ILD and pulmonary hypertension, such as scleroderma.

In general, the severity of the DLCO reduction does not correlate well with disease prognosis, unless the DLCO is less than 35 percent of predicted [28]. Longitudinal changes in DLCO have been used to assess disease progression or regression. Due to difficulties with reproducibility in measuring DLCO, a change of 15 percent is needed to identify a true change in disease severity [1].

Gas exchange at rest and on exertion — Resting arterial blood gases may be normal in early ILD or may reveal hypoxemia (secondary to mismatching of ventilation to perfusion) and respiratory alkalosis. Carbon dioxide retention is rare and usually a manifestation of end-stage disease. (See "Arterial blood gases".)

Normal values for resting arterial partial pressure of oxygen (PaO2) or pulse O2 saturation do not rule out significant hypoxemia during exercise or sleep. Thus, it is important to perform exercise testing with serial measurement of arterial blood gases or pulse oximetry (figure 3). Exercise testing may take the form of a cardiopulmonary exercise test, a six-minute walk test (6MWT), or informal ambulatory oximetry including a stair climb to replicate the patient's usual daily activity. (See "Overview of pulmonary function testing in adults", section on 'Pulse oxygen saturation'.)

Cardiopulmonary exercise testing – In a cardiopulmonary exercise test, arterial oxygen desaturation, a failure to decrease dead space appropriately with exercise (ie, a high dead space [VD]/tidal volume [VT] ratio), and an excessive increase in respiratory rate with a lower-than-expected recruitment of tidal volume provide useful information regarding physiologic abnormalities and the extent of disease. Full cardiopulmonary exercise testing is not necessary for every patient with ILD. However, when the significance of symptoms or radiographic abnormalities is unclear, a normal maximal cardiopulmonary exercise test effectively excludes significant ILD [1]. (See "Exercise physiology" and "Measures of oxygenation and mechanisms of hypoxemia".)

Serial assessment of pulse oxygen saturation – Serial assessment of resting and exercise gas exchange is one of the most used methods used to follow ILD activity and responsiveness to treatment, especially in idiopathic pulmonary fibrosis (IPF). As an example, the results of a 6MWT have correlated with prognosis in several studies of IPF [29-32]. Pulse oximetry desaturation to 88 percent or below during the 6MWT is associated with a median survival of 3.21 years compared with a median survival of 6.63 years in those who did not desaturate below 89 percent [30]. The distance walked during the 6MWT is a reproducible measure and correlates with the maximal oxygen consumption (VO2 max) obtained during a maximal exercise test [32]. Among patients with idiopathic pulmonary fibrosis, a heart rate recovery of less than 13 beats per minute by one minute after completion of a 6MWT is associated with a median survival of 1.96 years, compared with 3.2 years in patients with a faster heart rate recovery [33].

CARDIAC EVALUATION — It is prudent to assess cardiac function during the initial evaluation of interstitial lung disease (ILD), as heart failure is in the differential diagnosis of ILD. An electrocardiogram is typically obtained to evaluate for evidence of concurrent cardiac disease or pulmonary hypertension. If heart failure or pulmonary hypertension is suspected, a serum brain natriuretic peptide or N-terminal-proBNP level is measured. (See "Approach to the patient with dyspnea", section on 'Cardiovascular' and "Approach to the patient with dyspnea", section on 'Initial testing in chronic dyspnea'.)

There are no clear guidelines on when to obtain a transthoracic echocardiogram in a patient with ILD. A reasonable approach is to perform echocardiography in patients with an abnormal electrocardiogram, suspected heart failure, rapid onset of radiographic findings, or a moderate to severe reduction in diffusing capacity (DLCO). A low DLCO may suggest concomitant pulmonary hypertension. The presence of an abnormal heart rate recovery one minute after a 6MWT has also been associated with an increased likelihood of underlying pulmonary hypertension [34]. If it has not been performed previously, echocardiography is typically performed before obtaining a surgical lung biopsy to exclude occult heart failure. (See 'Diffusing capacity' above and "Tests to evaluate left ventricular systolic function" and "Clinical features and diagnosis of pulmonary hypertension of unclear etiology in adults", section on 'Echocardiography'.)

Assessment for concomitant pulmonary hypertension is important because the presence of pulmonary hypertension may be a clue to the underlying ILD etiology (eg, systemic sclerosis, mixed connective tissue disease) or severity. In addition, among patients with idiopathic pulmonary fibrosis (IPF), pulmonary hypertension is associated with increased disease severity and decreased survival. Doppler echocardiography has been shown to have a sensitivity as high as 88 percent for the diagnosis of pulmonary hypertension, but the correlation between Doppler echocardiogram-derived pulmonary artery systolic pressure (PASP) and right heart catheterization-derived PASP is lower in right-heart predominant disease [35,36]. Right heart catheterization may be appropriate in patients with a normal echocardiogram but a high clinical suspicion for pulmonary hypertension (eg, dyspnea or oxygen desaturation out of proportion to the degree of parenchymal lung disease). (See "Pulmonary hypertension due to lung disease and/or hypoxemia (group 3 pulmonary hypertension): Epidemiology, pathogenesis, and diagnostic evaluation in adults" and "Clinical features and diagnosis of pulmonary hypertension of unclear etiology in adults", section on 'Postdiagnostic testing and classification'.)

ROLE OF BRONCHOALVEOLAR LAVAGE — Bronchoalveolar lavage (BAL) is performed during flexible bronchoscopy to obtain samples of cells and fluid from the distal airways and alveoli [37]. The lavage fluid is sent for cell counts; cultures for mycobacterial, viral, and fungal pathogens; and cytologic analysis (table 8 and table 9 and table 10). BAL is particularly useful in the evaluation of patients with ILD that is associated with hemoptysis, is acute or rapidly progressive, or is likely caused by one of the following diseases: sarcoidosis, hypersensitivity pneumonitis, pulmonary Langerhans histiocytosis, or infection. (See "Role of bronchoalveolar lavage in diagnosis of interstitial lung disease".)

Virtually all patients presenting with hemoptysis and radiographic ILD should promptly undergo BAL with sequential lavages to confirm an alveolar source of bleeding and identify any infectious etiologies. (See "Role of bronchoalveolar lavage in diagnosis of interstitial lung disease", section on 'Hemorrhagic BAL' and "The diffuse alveolar hemorrhage syndromes".)

The majority of patients with an acute onset of ILD will undergo BAL to evaluate for acute eosinophilic pneumonia, alveolar hemorrhage, malignancy, and opportunistic or atypical infection, which can often be diagnosed on the basis of BAL findings (table 8). (See "Role of bronchoalveolar lavage in diagnosis of interstitial lung disease", section on 'Eosinophilic BAL' and "Role of bronchoalveolar lavage in diagnosis of interstitial lung disease", section on 'Hemorrhagic BAL' and "Approach to the immunocompromised patient with fever and pulmonary infiltrates", section on 'Invasive procedures'.)

For patients with a subacute or chronic presentation of ILD, BAL is often performed when sarcoidosis, hypersensitivity pneumonitis, pulmonary Langerhans cell histiocytosis (PLCH), or infection are suspected based on the radiographic pattern (eg, upper lobe predominance of reticular opacities, hilar lymphadenopathy, irregular cystic airspaces), history of exposure (eg, bird keeping, farming), or concomitant clinical findings (eg, hemoptysis, renal insufficiency). In these patients, the results of BAL analysis may be used to narrow the differential diagnostic possibilities between various types of ILD, but tissue confirmation is usually required (table 11). When PLCH is suspected, a sample of BAL fluid should be examined for Langerhans cells, which are CD-1a and CD207 positive; a finding of more than 5 percent CD-1a positive cells is strongly suggestive of PLCH. (See "Role of bronchoalveolar lavage in diagnosis of interstitial lung disease", section on 'Lymphocytic BAL' and "Pulmonary Langerhans cell histiocytosis", section on 'Flexible bronchoscopy'.)

BAL is less likely to be helpful in patients with a radiographic pattern suggestive of idiopathic pulmonary fibrosis (IPF) [14,20,38,39]. In the evaluation of patients with suspected IPF, the main role of BAL is to exclude chronic hypersensitivity pneumonitis. A BAL lymphocytosis >40 percent is suggestive of chronic hypersensitivity pneumonitis [39]. We do not typically perform BAL in patients with typical HRCT findings for IPF and have no identifiable exposure to agents that cause hypersensitivity pneumonitis based upon a thorough discussion of potential environmental and occupational exposures.

BAL does not have an established role in the assessment of ILD progression or response to therapy.

ROLE OF LUNG BIOPSY — When the results of the above evaluation do not allow the clinician to make a confident diagnosis of a given type or stage of ILD, lung biopsy with multidisciplinary interpretation of the results may be necessary [1,40]. The decision to pursue lung biopsy must be made on a case-by-case basis, weighing the morbidity of the procedure, the likely diagnoses, the toxicity of therapy, and the values and preferences of the patient. (See "Role of lung biopsy in the diagnosis of interstitial lung disease", section on 'Overview' and "Interpretation of lung biopsy results in interstitial lung disease", section on 'Multidisciplinary discussion' and "Clinical manifestations and diagnosis of idiopathic pulmonary fibrosis", section on 'How to decide whether a biopsy is necessary'.)

Indications – We typically obtain a lung biopsy in patients with atypical or progressive symptoms and signs (fever, weight loss, hemoptysis, signs of vasculitis), atypical radiographic features, unexplained extrapulmonary manifestations, rapid clinical deterioration, or sudden change in radiographic appearance.

Occasionally, the noninvasive evaluation will yield conflicting findings, which may require a lung biopsy for clarification. As an example, a cardiopulmonary exercise test may indicate that ILD is the most likely cause of a patient's symptoms and signs, while their high-resolution computed tomography (HRCT) shows only minimal interstitial changes. In this situation, a lung biopsy may be indicated to confirm that an ILD, rather than another process, is the cause of the patient's clinical findings, thus enabling appropriate treatment.

Lung biopsy may also be indicated to exclude neoplastic and infectious processes. As an example, sarcoidosis can sometimes have a similar HRCT appearance to lymphangitic carcinomatosis or hypersensitivity pneumonitis (table 7A-B). Or, a patient with rheumatoid arthritis might develop ILD due to the underlying disease, drugs used in treatment, or tuberculosis.

Patients with minimal symptoms, signs, physiologic impairment, and radiographic abnormalities may prefer close observation over several months with interval repetition of pulmonary function tests and HRCT, rather than proceeding immediately to lung biopsy. Other patients prefer to undergo a lung biopsy sooner to obtain a definitive diagnosis, rather than watchful waiting.

Selection of procedure – Lung biopsy may be obtained by flexible bronchoscopy, video-assisted thoracoscopic (VATS) biopsy, or thoracotomy. These techniques and the reasons to choose one over another are discussed separately. (See "Role of lung biopsy in the diagnosis of interstitial lung disease", section on 'Specimen collection'.)

Multidisciplinary evaluation of biopsy results – The histopathologic pattern found on the lung biopsy specimen is evaluated in combination with the clinical information to determine the diagnosis. The histopathologic patterns of common interstitial lung diseases are described separately. (See "Idiopathic interstitial pneumonias: Classification and pathology" and "Interpretation of lung biopsy results in interstitial lung disease", section on 'Interpretation of histopathologic patterns'.)

Genomic classifier -- A genomic classifier (Envisia genomic classifier) has been developed to assist in the diagnostic evaluation of patients with fibrotic lung disease to increase diagnostic confidence of the UIP pattern without having to resort to surgical lung biopsy [41,42]. The genomic classifier test uses total RNA extracted from biopsy samples to perform Next Generation RNA Sequencing. The gene count data from 190 genes are input to a machine learning algorithm that allows the separation of UIP from non-UIP. This test appears useful particularly for patients without a clear radiological diagnosis of the UIP pattern [43,44].

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Interstitial lung disease".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, “The Basics” and “Beyond the Basics.” The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on “patient info” and the keyword(s) of interest.)

Basics topics (see "Patient education: Idiopathic pulmonary fibrosis (The Basics)" and "Patient education: Interstitial lung disease (The Basics)")

SUMMARY AND RECOMMENDATIONS

Classification and causes – Diffuse parenchymal lung diseases (DPLD), often collectively referred to as interstitial lung diseases (ILDs), are a heterogeneous group of disorders that are classified together because of similar clinical, radiographic, physiologic, or pathologic manifestations. The classification of ILD is described in the algorithm (algorithm 1). (See 'Introduction' above.)

A broad range of diseases (table 1), exposures (table 2A-B), and drugs (table 3) are associated with or cause ILD. In addition, a number of ILDs are idiopathic (table 4). (See 'Causes of ILD' above.)

Diagnostic approach – The treatment choices and prognosis vary among the different causes and types of ILD, so ascertaining the correct diagnosis is important. An algorithm for evaluating a patient with ILD is provided in the figure (algorithm 2). (See 'Causes of ILD' above.)

Laboratory tests – The routine laboratory evaluation is often nonspecific, but should include biochemical tests to evaluate hepatic and renal function; complete and differential blood count to check for evidence of anemia, polycythemia, leukocytosis, or eosinophilia; urinalysis; and creatine kinase for myositis (table 5). Additional serologic testing is often obtained, based on the results of the clinical findings. (See 'Laboratory tests' above.)

Imaging – The diagnostic approach to ILD relies on high-resolution computed tomography (HRCT) of the chest. Image acquisition should be tailored for ILD evaluation, which differs from conventional chest CT protocols. Intravenous contrast is usually not administered. (See 'Computed tomography' above and "High resolution computed tomography of the lungs".)

Certain HRCT findings help to narrow the differential diagnosis of ILD. The correlations between the various HRCT patterns and likely diagnoses are shown in the table (table 7A-B). (See 'Computed tomography' above and "High resolution computed tomography of the lungs".)

Cardiac evaluation – An electrocardiogram is typically obtained to evaluate for evidence of pulmonary hypertension or concurrent cardiac disease. If heart failure is suspected, a serum brain natriuretic peptide (BNP) level is measured. An echocardiogram is also obtained when there is suspicion for heart failure or pulmonary hypertension. (See 'Cardiac evaluation' above.)

Pulmonary function tests – Complete lung function testing (spirometry, lung volumes, diffusing capacity) and exercise pulse oximetry (eg, during six-minute walk test) are obtained in all patients with suspected ILD. Resting room air arterial blood gases are often obtained to corroborate findings of pulse oximetry. (See 'Pulmonary function testing' above.)

Bronchoalveolar lavage – The majority of patients with an acute onset of ILD should undergo bronchoalveolar lavage (BAL) to evaluate for alveolar hemorrhage, eosinophilia, malignancy, and opportunistic or atypical infection.

BAL is performed promptly in patients with hemoptysis and radiographic ILD to confirm an alveolar source of bleeding and identify infectious etiologies, if present.

In patients with a more chronic presentation of ILD, the BAL is less helpful, as the findings are typically nonspecific. However, when sarcoidosis, hypersensitivity pneumonitis, pulmonary Langerhans histiocytosis, or infection are suspected based on the radiographic pattern, history of exposure, or concomitant clinical findings, BAL may help to narrow the differential diagnosis. (See 'Role of bronchoalveolar lavage' above and "Role of bronchoalveolar lavage in diagnosis of interstitial lung disease".)

Lung biopsy – When it is not possible to make a confident diagnosis or to stage the disease after an initial noninvasive evaluation, lung biopsy with careful examination of lung tissue may be necessary. This decision is made on a case-by-case basis, weighing the morbidity of the procedure, the likely diagnoses, the toxicity of therapy, and the values and preferences of the patient. (See 'Role of lung biopsy' above and "Role of lung biopsy in the diagnosis of interstitial lung disease".)

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Topic 4358 Version 22.0

References

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