INTRODUCTION — The diffuse parenchymal lung diseases, 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). The results of clinical assessment, laboratory tests, imaging, and pulmonary function tests guide the decisions about whether to pursue transbronchoscopic, thoracoscopic, or surgical lung biopsy, as outlined in the algorithm (algorithm 2).
The indications and methods for obtaining lung biopsies to evaluate ILD will be reviewed here. The clinical evaluation, diagnostic testing, role of bronchoalveolar lavage, and histopathologic patterns commonly encountered in adults with suspected ILD are discussed separately. (See "Approach to the adult with interstitial lung disease: Clinical evaluation" and "Approach to the adult with interstitial lung disease: Diagnostic testing" and "Basic principles and technique of bronchoalveolar lavage" and "Role of bronchoalveolar lavage in diagnosis of interstitial lung disease".)
OVERVIEW — When the results of clinical evaluation, laboratory testing, imaging studies including high-resolution computed tomography (HRCT), and pulmonary function testing do not allow the clinician to make a confident diagnosis of a given type or stage of ILD, lung biopsy with careful examination of lung tissue is often necessary (algorithm 2) [1,2]. The evaluation of ILD leading up to lung biopsy is described separately. (See "Approach to the adult with interstitial lung disease: Clinical evaluation" and "Approach to the adult with interstitial lung disease: Diagnostic testing".)
Indications — Lung biopsy is generally helpful in the evaluation of patients with ILD in the following situations:
●To provide a specific diagnosis. This is especially desirable in a patient with clinical features such as age <50 years, fever, weight loss, hemoptysis, or signs of vasculitis; a progressive course; atypical or rapidly changing HRCT findings; unexplained extrapulmonary manifestations; or pulmonary vascular disease of unclear origin.
●To exclude neoplastic and infectious processes that can mimic chronic, progressive ILD.
●To identify a more treatable process than originally suspected (eg, hypersensitivity pneumonitis versus idiopathic pulmonary fibrosis).
●To predict the likelihood of response to therapy before proceeding with therapies that may have serious side effects (eg, cellular nonspecific interstitial pneumonia or organizing pneumonia versus idiopathic pulmonary fibrosis) .
●Rarely, to diagnose ILD in a patient with hypoxemia, pulmonary function tests strongly suggestive of ILD, a negative evaluation for pulmonary vascular disease, and a normal HRCT.
Lung tissue can be obtained via transbronchial biopsy (TBLB), transbronchial cryobiopsy (cryo-TBB), thoracotomy, or video-assisted thoracoscopic surgery (VATS). The specific settings in which one procedure is preferred over the others are discussed below. (See 'Transbronchial lung biopsy' below and 'When is lung biopsy unlikely to be helpful?' below.)
Patient preference must also be considered. Patients with minimal symptoms, signs, physiologic impairment, and radiographic abnormality 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 and clarify their prognosis, rather than watchful waiting.
Relative contraindications — Patients with relative contraindications to lung biopsy should be evaluated on a case-by-case basis to be sure that the procedure is likely to reveal a treatable diagnosis at an acceptable level of risk and that less invasive methods will not yield a diagnosis. As examples, patients with an underlying solid or hematologic malignancy may have ILD that is not treatable (eg, fibrotic pneumonitis due to irradiation) and immunosuppressed patients may have a diagnosis that can be determined by less invasive methods (eg, bronchoalveolar lavage).
Relative contraindications to lung biopsy include:
●Radiographic evidence of diffuse end-stage disease, eg, "honeycombing," without areas of milder disease activity, as biopsy of end-stage fibrosis is unlikely to reveal an etiology.
●Extensive pleural disease or emphysema that increase the risk of biopsy.
●Severe pulmonary dysfunction manifest by a diffusing capacity (DLCO) less than 35 percent predicted, severe hypoxemia needing supplemental oxygen, or respiratory failure requiring mechanical ventilation.
●Serious cardiovascular disease, advanced age , bleeding disorder, or other major risks for surgery or general anesthesia.
Transbronchial cryobiopsy or transbronchial lung biopsy may be performed in selected patients who are not candidates for surgical lung biopsy due to one or more of these factors, but in whom a diagnosis may substantially alter therapy or prognosis.
TRANSBRONCHIAL LUNG BIOPSY — Transbronchial lung biopsies (TBLB) are obtained during flexible bronchoscopy, using biopsy forceps that are passed through the channel of the bronchoscope. The equipment and technique of flexible bronchoscopy with TBLB are discussed separately. (See "Flexible bronchoscopy in adults: Overview" and "Flexible bronchoscopy in adults: Associated diagnostic and therapeutic procedures", section on 'Transbronchial biopsy'.)
When is TBLB most helpful? — TBLB is often the biopsy procedure of choice when the suspected ILD is likely to have a centrilobular location (image 1) and when a diagnosis can be made from small samples of lung tissue . Examples of centrilobular diseases include sarcoidosis, hypersensitivity pneumonitis, lymphangitic carcinomatosis, eosinophilic pneumonia, and alveolar proteinosis [5-8]. Infection can often be diagnosed on a small biopsy sample. (See "High resolution computed tomography of the lungs", section on 'Centrilobular nodules' and "Approach to the adult with interstitial lung disease: Clinical evaluation" and "Approach to the adult with interstitial lung disease: Diagnostic testing".)
Sarcoidosis tends to have a centrilobular distribution and a characteristic histopathologic finding of diffuse noncaseating granulomas, giving TBLB a high likelihood of diagnostic success in suspected sarcoidosis. The benefit of TBLB was demonstrated in a series of 150 patients with suspected sarcoidosis: 88 patients had granulomas on TBLB, an additional 10 had granulomas on endobronchial biopsy, and 9 had findings diagnostic of another disease, bringing the overall rate of diagnosis to 71 percent . (See "Clinical manifestations and diagnosis of sarcoidosis".)
A positive TBLB with typical histopathologic findings can also be diagnostic in a small subset of patients with subacute hypersensitivity pneumonitis, cryptogenic organizing pneumonia, or pulmonary alveolar proteinosis in the context of an appropriate clinical presentation and typical HRCT findings [5,10-12]. These patients should be followed closely and further diagnostic procedures (eg, a surgical lung biopsy) should be considered if their temporal course or response to therapy is inconsistent with the working diagnosis . (See "Hypersensitivity pneumonitis (extrinsic allergic alveolitis): Clinical manifestations and diagnosis", section on 'Surgical lung biopsy' and "Causes, clinical manifestations, and diagnosis of pulmonary alveolar proteinosis in adults", section on 'Diagnostic evaluation' and "Cryptogenic organizing pneumonia", section on 'Invasive testing to rule out alternative diagnoses'.)
TBLB is less likely to be helpful when the pattern on high-resolution computed tomography (HRCT) is indeterminant or suggests an idiopathic interstitial pneumonia (algorithm 2). (See "Idiopathic interstitial pneumonias: Classification and pathology".)
What are the diagnostic limitations? — TBLB are a few millimeters in size and are subject to crush artifact. They may miss the correct diagnosis when the disease is patchy or when visualization of whole pulmonary acini is needed to fully evaluate disease distribution. Examples include granulomatosis with polyangiitis and other vasculitides that typically require examination of arteries and arterioles that are larger than those obtained by TBLB and the idiopathic interstitial pneumonias, particularly idiopathic pulmonary fibrosis.
Idiopathic pulmonary fibrosis — TBLB cannot be used to make a conclusive diagnosis of idiopathic pulmonary fibrosis (IPF), based on the absence of prospective studies utilizing an acceptable gold standard that demonstrates the usefulness of TBLB in the diagnosis of usual interstitial pneumonia (UIP), the histologic pattern associated with IPF [13-16]. While transbronchial biopsy is rarely sufficient to make a pathological diagnosis of UIP, a properly performed and interpreted transbronchial biopsy that is negative for an alternative diagnosis does increase the post-test probability of idiopathic pulmonary fibrosis in patients who already have a high pre-test probability of IPF .
The reason that TBLB is unsuccessful in the diagnosis of IPF is that the histopathologic diagnosis of UIP depends on the low power visualization of gross architectural features such as the repetitive combination of patchy fibrosis, fibroblastic foci, and microscopic honeycombing with intervening normal lung parenchyma, changes that cannot be appreciated on a transbronchial biopsy . Additionally, areas of more diffuse fibrotic nonspecific interstitial pneumonia (NSIP)-like fibrosis, that are commonly seen in UIP can easily be distinguished on a surgical lung biopsy, but not on a transbronchial biopsy .
Varying combinations of histopathologic findings suggestive of UIP, including fibroblastic foci, patchy interstitial fibrosis, and honeycombing, have been demonstrated in a minority of transbronchial biopsy studies. In a retrospective series, features of UIP were present in 12/30 TBLB specimens from patients who had definite UIP for a sensitivity of 30 percent .
Importantly, individual features of UIP such as honeycombing or fibroblastic foci in themselves are not specific for UIP and can be found in other disorders, such as drug reactions, chronic hypersensitivity pneumonitis, rheumatic diseases, and asbestosis .
Non-IPF idiopathic interstitial pneumonias — In the idiopathic interstitial pneumonias (IIPs) (table 1), histopathologic pattern and distribution are key to the diagnosis, and studies have found a low diagnostic yield in patients with IIP undergoing transbronchial biopsy [5,6]. We suggest not pursuing TBLB in patients suspected of having an IIP, particularly IPF (see 'Idiopathic pulmonary fibrosis' above). However, a potential exception is suspected cryptogenic organizing pneumonia, in which a TBLB with typical histopathologic findings might be sufficient in the appropriate clinical and radiologic context . (See 'When is TBLB most helpful?' above.)
The histopathologic features of the various IIPs are discussed separately. (See "Idiopathic interstitial pneumonias: Classification and pathology".)
Safety — TBLB is a safe, minimally invasive procedure with an estimated mortality of <0.05 percent [5,9,18]. Pneumothorax is estimated to occur in 0.7 to 2 percent, although rates up to 10 percent have been reported; less than half require tube thoracostomy drainage [1,5,14,18,19]. Bleeding (>50 mL) is reported in 1 to 4 percent . Additional information about the risks of TBLB and bronchoscopy in general and precautions to minimize procedure-related bleeding are provided separately. (See "Flexible bronchoscopy in adults: Overview" and "Flexible bronchoscopy in adults: Preparation, procedural technique, and complications", section on 'Complications'.)
Specimen collection and diagnostic yield — In patients with ILD, the location selected for TBLB is generally an area that appears involved on HRCT. Of note, it is general practice NOT to perform bilateral transbronchial biopsies during a single bronchoscopy because of the risk of bilateral iatrogenic pneumothorax. Specimens that float are no more likely to be diagnostic than those that do not float . The role of fluoroscopic guidance during TBLB is discussed separately. (See "Flexible bronchoscopy in adults: Associated diagnostic and therapeutic procedures", section on 'Transbronchial biopsy'.)
●Cupped versus toothed forceps – The data are conflicting on whether diagnostic yields are greater with cupped or toothed forceps. Larger TBLB specimens are more likely to yield diagnostic information.
•In a trial that randomly assigned 150 patients undergoing TBLB for suspected sarcoidosis to use of cup forceps or toothed (alligator) forceps, the rate of positive biopsies was not different between the groups, although complications were slightly lower with toothed forceps .
•A separate trial randomly assigned 44 patients to cupped or toothed forceps and four biopsies were obtained from each patient . While the size of the biopsies was slightly greater with toothed forceps, the rate of diagnosis was not different between the groups. Pneumothorax and bleeding occurred slightly more often with cupped forceps.
•In an earlier series that examined 170 TBLB specimens, toothed forceps typically provided larger specimens than cupped forceps and were more likely to yield diagnostic information .
●Number of TBLB specimens – The optimal number of TBLB specimens reflects a balance between the expected diagnostic yield and the patient's tolerance of the procedure. Usually, four to six TBLB specimens are obtained [5,19,20,22-24]. The effect of the number of transbronchial biopsies on diagnostic yield has been examined in case series, although the data are influenced by the underlying ILD. Among 244 patients with diffuse ILD, the diagnostic yield was 50 percent, based on five to six biopsies . In a series of 24 patients with interstitial lung disease, 118 biopsies were obtained (average five per patient) of which 78 percent were of adequate quality and gave an overall diagnostic yield of 74 percent .
Ancillary tests — When performing flexible bronchoscopy in patients with interstitial lung disease, endobronchial biopsy and bronchoalveolar lavage (BAL) are often performed during the same procedure as TBLB although the data in support of this practice are limited. Transbronchial needle aspirate of enlarged mediastinal or hilar lymph nodes using an ultrasound guided probe can also be performed during the same procedure if the appropriate equipment is available.
●Endobronchial biopsy – Endobronchial mucosal biopsies can be helpful in patients suspected of having sarcoidosis or chronic beryllium disease. Four to six endobronchial biopsies are usually obtained, preferably from a site where the mucosa appears erythematous or from the first and secondary carinas if the mucosa appears normal . In sarcoidosis, endobronchial mucosal biopsies are frequently positive and may increase the diagnostic yield, compared with transbronchial biopsies alone [9,26]. In a series of 37 patients with sarcoidosis, endobronchial biopsies had a diagnostic yield of 24 percent and increased the yield over transbronchial biopsy alone by 8 percent. (See "Chronic beryllium disease (berylliosis)", section on 'Endobronchial and transbronchial biopsy' and "Clinical manifestations and diagnosis of sarcoidosis".)
●Bronchoalveolar lavage – Results of BAL are generally not diagnostic in ILD, but frequently provide supportive evidence for or against a diagnosis. We typically perform BAL after obtaining the TBLB specimens and avoid performing BAL in the same subsegments as the TBLB. The role of BAL in the evaluation of ILD and the analysis of lavage fluid are discussed separately. (See "Flexible bronchoscopy in adults: Overview" and "Role of bronchoalveolar lavage in diagnosis of interstitial lung disease".)
●Ultrasound-guided transbronchial needle aspiration of mediastinal or hilar lymph nodes – Endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) requires a special bronchoscope and is performed under general anesthesia, typically with a laryngeal mask airway in place. It is performed to evaluate enlarged hilar and mediastinal lymph nodes. The bronchoscope for EBUS is different from the standard bronchoscope used for TBLB, but general anesthesia and the laryngeal mask airway make it relatively easy to change bronchoscopes and perform both EBUS-TBNA and TBLB during a single procedure . (See "Endobronchial ultrasound: Indications, contraindications, and complications".)
EBUS-TBNA has a yield of 90 to 96 percent for the diagnosis of sarcoidosis in the presence of hilar or mediastinal adenopathy. The technique of EBUS-TBNA is described separately. (See "Bronchoscopy: Transbronchial needle aspiration", section on 'Technical considerations' and "Endobronchial ultrasound: Technical aspects".)
DECISION TO PERFORM MORE INVASIVE BIOPSIES — Surgical lung biopsy (SLB) and transbronchial cryobiopsy (cryo-TBB) allow for larger specimens and higher diagnostic yield in patients with unclassifiable ILD based on clinical, laboratory, and radiographic features. However, these procedures carry increased risk of morbidity and adverse events and are not appropriate for all patients.
When is lung biopsy unlikely to be helpful? — Not all patients with ILD need a lung biopsy because the combination of history, physical examination, radiologic imaging, physiologic testing, and other ancillary testing is sufficiently diagnostic, especially when combined with multidisciplinary evaluation. A lung biopsy in these patients adds little diagnostic and prognostic information, does not change therapy, and should be avoided. Two specific subpopulations in which surgical lung biopsy is generally not necessary are patients with a known systemic rheumatic disease and patients presenting with previously undiagnosed ILD and respiratory failure.
Interstitial lung disease associated with systemic rheumatic disease — Lung biopsy should generally be avoided in patients with ILD associated with a systemic rheumatic disease. It is uncommon for histopathologic information to provide information that cannot be obtained by noninvasive means, and the treatment for ILD associated with systemic rheumatic disease is generally dictated by factors such as extent of disease, physiologic impairment, and rate of progression rather than the underlying histopathology [28-33]. In patients with RA undergoing lung biopsy, the proportions of patients with UIP, NSIP, and bronchiolar disease are approximately 30 percent each [32,34-36]. Lung biopsy is rarely needed in SSc-associated ILD. (See "Interstitial lung disease in rheumatoid arthritis", section on 'Lung biopsy' and "Clinical manifestations, evaluation, and diagnosis of interstitial lung disease in systemic sclerosis (scleroderma)", section on 'Evaluation'.)
Interstitial lung disease presenting with acute respiratory failure — For patients with acute respiratory failure due to an ILD with a rapidly progressive or accelerated course or an acute exacerbation of underlying ILD, a lung biopsy may be the only diagnostic modality likely to reveal a treatable diagnosis. However, most surgical biopsies in such patients do not lead to a better outcome due to diagnostic and therapeutic limitations and the increased perioperative morbidity and mortality of the procedure. (See 'Morbidity and mortality' below.)
Most surgical lung biopsy data in patients with respiratory failure come from patients with acute respiratory distress syndrome (ARDS) and immunocompromised patients with pulmonary opacities and respiratory failure [37-51]. Infection and malignancy are the most common specific diagnoses made on surgical lung biopsy in these patients. Given the high likelihood of infection or malignancy, it is worth considering whether a less invasive method would yield a diagnosis. Bronchoalveolar lavage (BAL) identifies the majority of pulmonary infections and has high sensitivity and negative predictive value with performance characteristics comparable with that of surgical lung biopsy to exclude pulmonary infections [43,49,52,53]. Diffusely metastatic pulmonary malignancy can often be diagnosed with transbronchial biopsy.
When a lung biopsy reveals a noninfectious and nonmalignant diagnosis, the diagnosis may not be useful therapeutically. Noninfectious and nonmalignant diagnoses are often reported using nonspecific terms such as fibrosis, nonspecific pneumonitis, chronic pneumonitis, interstitial fibrosis, interstitial pneumonitis, and interstitial pulmonary fibrosis that are insufficient to guide specific therapy [37-51].
Acute exacerbations of fibrotic interstitial lung diseases have been described in idiopathic pulmonary fibrosis (IPF), rheumatic disease-associated UIP or NSIP, idiopathic NSIP, chronic hypersensitivity pneumonitis, desquamative interstitial pneumonia (DIP), and asbestosis. The patients' clinical presentation is with an acute/subacute worsening of symptoms and hypoxemia. The diagnosis of acute exacerbation of ILD is based on exclusion, primarily of infection, heart failure, drugs, or aspiration. Biopsies from such patients generally show diffuse alveolar damage or organizing pneumonia superimposed on an underlying fibrotic process, which can often be hard to diagnose because of the acute findings [54,55]. Additionally, it is unclear that a biopsy would affect therapeutic decisions in these patients because acute exacerbations of IPF and other ILDs are often treated with high-dose glucocorticoids irrespective of the biopsy results and generally have poor outcomes despite treatment [54,56-62]. (See "Acute exacerbations of idiopathic pulmonary fibrosis".)
Radiologic pattern and decision to perform lung biopsy — Radiologic pattern on HRCT is an important consideration when deciding whether a patient should undergo a surgical lung biopsy [63,64]. (See "Approach to the adult with interstitial lung disease: Diagnostic testing", section on 'Computed tomography' and "Clinical manifestations and diagnosis of idiopathic pulmonary fibrosis", section on 'How to decide whether a biopsy is necessary'.)
The following considerations regarding the role of invasive lung biopsy apply to patients whose interstitial lung disease remains undiagnosed despite a thorough multidisciplinary assessment (see "Interpretation of lung biopsy results in interstitial lung disease"):
UIP pattern — A UIP pattern demonstrates basal predominant (occasionally diffuse) and subpleural predominant, often heterogeneous reticular opacities with peripheral traction bronchiectasis or bronchiolectasis, honeycombing, and absence of features to suggest an alternative diagnosis [63,64]. A UIP pattern on HRCT is very specific in predicting a UIP pattern on histopathology. A lung biopsy is therefore not recommended in patients with a UIP pattern on CT [63,64].
Probable UIP pattern — The "probable" UIP pattern on HRCT is similar to that of a UIP pattern except honeycombing is absent, ie, reticular opacities are predominantly basal and subpleural, with peripheral traction bronchiectasis or bronchiolectasis and a heterogeneous distribution [63,64]. Features suggestive of an alternative diagnosis are notably absent.
The 2022 American Thoracic Society (ATS), European Respiratory Society (ERS), Japanese Respiratory Society (JRS), and Latin American Thoracic Society (ALAT) guidelines suggest that a lung biopsy is not necessary in patients with an HRCT pattern considered definite or probable for UIP when a multidisciplinary discussion yields a confident diagnosis of IPF . This approach requires an assessment of both the HRCT pattern and the larger clinical context.
In our clinical practice, we divide patients with a probable UIP pattern into two categories based on the pretest probability of IPF, confidence in the radiologic interpretation, and the estimated risk of postoperative morbidity and mortality from a surgical lung biopsy.
●We do not perform a surgical lung biopsy in patients who have a high pretest probability of IPF (for example, an older male smoker without other risk factors for ILD), when the HRCT pattern is made with high confidence, and when the estimated risk for postoperative morbidity and mortality is high because of comorbidities or severe physiologic restriction.
●We offer surgical lung biopsy to our patients with a probable UIP pattern on HRCT when the pretest probability of IPF is lower (for example, a younger patient with potential risk factors for another cause of ILD), and when the estimated risk for postoperative morbidity and mortality is low (absence of significant comorbidities and severe physiologic restriction). It is not uncommon for us to find alternative pathology such as hypersensitivity pneumonitis on the biopsy in these patients.
Indeterminate UIP pattern — The opacities in the "indeterminate" UIP pattern are variable or diffuse, and there is evidence of fibrosis with some inconspicuous features suggestive of non-UIP pattern. The indeterminate UIP radiographic pattern is neither sensitive nor specific for UIP or other alternative findings on histopathology, and a surgical lung biopsy should be considered if a specific diagnosis cannot otherwise be made, unless contraindications are present [63,64].
Radiologic pattern suggestive of alternative diagnosis — The previous label of "not UIP" pattern has been changed to pattern suggestive of an "alternative diagnosis" because a subset of patients with a histopathologic finding of UIP have CT patterns that suggest non-IPF diagnoses [63,64]. These radiologic findings include upper-lung or mid-lung predominant fibrosis, peribronchovascular predominance with subpleural sparing, predominant consolidation, extensive ground-glass opacity (without acute exacerbation), extensive mosaic attenuation with sharply defined lobular air trapping on expiration, and diffuse nodules or cysts. A surgical lung biopsy should be offered to patients with this radiologic pattern if a specific diagnosis cannot otherwise be made, unless contraindications are present [63,64].
In the uncommon situation where the radiologic pattern shows extensive fibrosis and architectural distortion (and does not have any of the other features described above such as ground-glass opacities), a surgical lung biopsy is generally not indicated because it is unlikely to alter management.
TRANSBRONCHIAL CRYOBIOPSY — Transbronchial cryobiopsy (cryo-TBB), which is performed under moderate sedation or general anesthesia, is a technique to obtain biopsy samples of lung parenchyma that exceed the size and quality of forceps biopsy samples [66-72].
Procedure — Cryobiopsies are obtained using a specialized, flexible probe that uses nitrous oxide to rapidly cool the tip to -89˚C, thus freezing adjacent tissue that is then removed attached to the tip of the probe. Cryo-TBB yields larger size biopsy specimens (43 to 64 mm2) compared with transbronchial biopsy (5.8 mm2, range 0.58 to 20.88 mm2) without crush artifacts, and therefore appears more likely to yield diagnostic information in support of a specific ILD [66,73,74]. The accuracy of cryo-TBB samples improves considerably when two or more samples are reviewed (instead of only one) and when biopsy is obtained in two different sites (instead of only one site), either from the same lobe or from different lobes (obtaining samples from different lobes is advised when there is inter-lobar radiographic heterogeneity) .
Additional study is needed to clarify procedural issues such as the optimal duration of freezing time, the distance from the pleural to optimize safety and yield, and also the number of segments and ipsilateral lobes that can be safely biopsied in one procedure [70,72,76,77]. The procedure is described in greater detail separately. (See "Flexible bronchoscopy in adults: Associated diagnostic and therapeutic procedures", section on 'Transbronchial biopsy' and "Bronchoscopic cryotechniques in adults", section on 'Cryobiopsy'.)
When is cryo-TBB most helpful? — International guidelines stress that the use of cryo-TBB for the diagnosis of ILD should only be performed in high-volume centers with standardized protocols to minimize risk and maximize yield, as well as experienced personnel for performing biopsies and providing pathologic interpretation of small samples [65,78]. In these centers of expertise, cryo-TBB offers the possibility of improved safety and only modestly decreased diagnostic yield compared with surgical approaches [67,68,79,80]. We do not consider cryo-TBB to be a replacement for the currently accepted gold standard for diagnosis of ILD, ie, surgical lung biopsy with multidisciplinary discussion and consensus diagnosis [31,36].
Although larger pieces of tissue can be obtained with cryobiopsy than Transbronchial lung biopsies (TBLB), some limitations of the bronchoscopic approach remain. These include nondiagnostic samples in patchy disease or when pleural/subpleural pathology adds critical diagnostic information . We therefore reserve cryo-TBB for central, peribronchial, or diffuse interstitial processes. Cryo-TBB results should also be reviewed in the context of multidisciplinary discussion to establish a specific ILD diagnosis. Subsequent surgical lung biopsy may be appropriate in patients who have nondiagnostic cryo-TBB samples. (See "Clinical manifestations and diagnosis of idiopathic pulmonary fibrosis", section on 'Multidisciplinary discussion and next steps'.)
Cryo-TBB may also be helpful with occasional patients at high risk for adverse events with surgical lung biopsy, but for whom histopathologic information is highly likely to change management. One study compared adverse outcomes after cryo-TBB in 58 patients at low risk for surgical lung biopsy (SLB) and 38 patients with high risk of SLB based on age ≥75 years, body mass index (BMI) ≥35 kg·m−2, systolic pulmonary arterial pressure (sPAP) by echocardiography ≥45 mmHg, forced vital capacity (FVC) <50 percent, diffusing capacity of the lung for carbon monoxide (DLCO) <30 percent and/or heart failure with reduced ejection fraction . Bleeding, pneumothorax, mortality and length of hospital stay were equal between the two groups.
However, the advantages of potentially increasing diagnostic certainty should be carefully weighed against the potential for adverse events. This is particularly true in patients with critical illness or rapidly progressive ILD, for whom procedural risk is higher than for patients with chronic comorbidities. (See 'Interstitial lung disease presenting with acute respiratory failure' above.)
Comparison with surgical lung biopsy
Diagnostic yield — In general, the diagnostic yield of cryo-TBB is less than with SLB (approximately 80 percent compared with 90 percent for SLB), although study results vary [71,79,81,83,84].
●Two studies have directly compared cryo-TBB and SLB yields. The COLDICE prospective study obtained both cryo-TBB and SLB specimens from 65 patients with ILD and found histopathologic concordance in 70 percent . Low-confidence or unclassifiable cryo-TBB diagnoses were reported in 26 patients (40 percent) and of these SLB reclassified six (23 percent) to alternative high-confidence or definite diagnoses after multidisciplinary discussion (MDD). In a separate study comparing cryo-TBB with SLB, pathological results were discordant in 11 of 21 patients (52 percent) .
●In a prospective, multicenter study of 128 patients with suspected idiopathic interstitial pneumonia, cryo-TBB increased the frequency of high confidence in the diagnosis (≥70 percent likelihood) from 60 to 81 percent, and the frequency of a confident diagnosis (≥90 percent likelihood) from 23 percent after bronchoalveolar lavage to 54 percent after cryo-TBB . Cryo-TBB was complicated by pneumothorax in 21 patients (16.4 percent) and moderate to severe bleeding in 20 patients (15.7 percent).
●In one single-center prospective cohort study of 141 patients with unclassifiable ILD after multidisciplinary discussion, outpatient cryo-TBB facilitated a pathologic diagnosis in 75 percent of patients and a clinical diagnosis (after multidisciplinary discussion) in 88 percent . Idiopathic interstitial pneumonias constituted the majority (67.3 percent) of the clinical diagnoses.
●In a retrospective study of 699 patients with diffuse parenchymal lung disease, a specific diagnosis was determined by cryo-TBB in 88 percent and a MDD diagnosis in 90 percent .
Safety — While the procedure is generally free of major complications , pneumothorax (2.6 to 30 percent), moderate bleeding (4 to 78 percent), ILD exacerbation, and rarely death (0.3 to 1.4 percent) have been reported [67,68,71,74,81,86-93]. In the single-center study described above (n = 141), cryo-TBB was complicated by pneumothorax in 21 patients (14.9 percent), moderate bleeding in 20 patients (15.7 percent), and two deaths (1.4 percent) within 30 days of cryo-TBB .
Despite the reported complications, the procedure is generally safer than SLB .
SURGICAL LUNG BIOPSY — Surgical lung biopsy (SLB) specimens can be obtained by video assisted thoracoscopic surgery (VATS) or thoracotomy [94,95]. Surgical specimens are substantially larger than those obtained by transbronchial lung biopsy (TBLB). Reported diagnostic yields vary, but are in the range of 85 to 92 percent [5,94-97]. In general the choice of procedure is based on the surgeon's expertise and preference, although thoracotomy is occasionally required instead of VATS because of severe pleural disease, anticipated bleeding, or more severe respiratory impairment. When SLB is necessary in patients with severe hypoxemia or requiring mechanical ventilation, thoracotomy is generally preferred because one lung ventilation is not absolutely necessary, whereas VATS requires a period of one lung ventilation. (See "Overview of minimally invasive thoracic surgery".)
Ideally, SLB is performed prior to the initiation of systemic glucocorticoids or other immunosuppressive therapy . However, a biopsy can often provide a histopathologic diagnosis after initiation of such therapies .
Surgical approach — Surgical lung biopsy specimens can be obtained via video assisted thoracoscopic surgery (VATS) or thoracotomy. The choice between these procedures is typically determined by the expertise and preference of the thoracic surgeon, although the majority are performed by VATS. While VATS appears to be associated with less morbidity overall, thoracotomy may be preferred in the setting of severe pleural disease, a bleeding diathesis, or mechanical ventilation.
VATS — VATS is a minimally invasive form of thoracic surgery performed under general anesthesia. One lung ventilation is employed during the biopsy procedure, so the lung being biopsied is deflated and respiratory movement inhibited. A rigid or semi-rigid thoracoscope and forceps for lung biopsy are typically introduced into the pleural space through one or two small incisions usually on the lateral chest wall. (See "Overview of minimally invasive thoracic surgery" and 'One lung ventilation' below.)
Thoracotomy — Thoracotomy, also performed under general anesthesia, requires a surgical incision of 5 to 6 cm. One lung ventilation can be used during the procedure, so the lung being biopsied is deflated and respiratory movement inhibited.
Alternatively, for patients with more advanced lung disease or those on mechanical ventilation who cannot tolerate single lung ventilation, lung biopsy can be obtained through a thoracotomy incision without deflation of the lung being biopsied. The thoracotomy incision allows the surgeon to palpate the lung texture but does not necessarily allow biopsy of areas of the lung remote from the incision.
VATS versus thoracotomy — VATS is preferred over thoracotomy because morbidity appears to be less with VATS [2,99-101]. Specimen adequacy and diagnostic accuracy are the same with the two procedures, although it is technically easier to obtain multilobe lung biopsies by VATS than by thoracotomy [5,99]. On the other hand, thoracotomy may be preferred in the presence of patient factors such as extensive pleural disease, bleeding disorder, and severe respiratory impairment causing inability to tolerate one lung ventilation.
Data from small trials suggest that morbidity and mortality are the same or slightly lower for VATS compared with thoracotomy [102,103]. A prospective, randomized trial comparing the two procedures found no difference in morbidity or mortality, however the study was small (42 patients) . A separate randomized trial of 61 patients reported reduced need for postoperative analgesia, shorter duration of chest tube drainage, and shorter hospital stay with VATS, but no difference in diagnostic yield or complication rates .
Looking at case series, complication rates and mortality are the same or lower for VATS than for thoracotomy, but the actual difference is likely less than the reported rates for several reasons. First, almost all of these data are retrospective and thoracotomy may have been performed instead of VATS because pleural adhesions or severe hypoxemia preclude the single lung ventilation needed for VATS. Such patients are likely to be at higher risk of complications and mortality. Second, most of the thoracotomy data comes from before 1992 and most of the VATS data comes from after 1992; improvement in intraoperative and postoperative care possibly contributed in some measure to the difference in mortalities. Third, most immunocompromised patients with respiratory failure, the group with the highest mortality, underwent thoracotomy instead of VATS, further skewing the mortality and complication rates in favor of VATS.
One lung ventilation — One lung ventilation (also known as single lung ventilation) is used during most surgical lung biopsy procedures to deflate the lung being biopsied for visualization and access. The transition from dual to one lung ventilation requires a balance between providing adequate ventilation to avoid hypoxemia and hypercapnia and preventing volutrauma and barotrauma caused by high tidal volumes or high plateau pressures. Lung protective ventilation is a key component of this process. (See "One lung ventilation: General principles" and "Diagnosis, management, and prevention of pulmonary barotrauma during invasive mechanical ventilation in adults".)
The importance of the lung protective ventilation is evident in the observation that patients are more likely to develop postoperative noncardiogenic pulmonary edema in the lung contralateral to the biopsy/resection site, ie, the ventilated lung rather than the collapsed lung. While the exact mechanism is not known, the predilection for the contralateral side suggests that ventilator-induced lung injury during the one lung ventilation may play a role [104-106]. In theory, intraoperative low tidal volume ventilation with maintenance of a low plateau pressure may be protective. The technique of one lung ventilation is discussed separately. (See "One lung ventilation: General principles".)
Due to poor lung compliance in patients with pulmonary fibrosis, increasing the positive end-expiratory pressure (PEEP) may not lead to lung recruitment and improved ventilation . Careful attention to keeping the plateau pressure to a minimum level required for adequate oxygenation is essential when increasing PEEP in response to hypoxemia. (See "Anesthesia for patients with interstitial lung disease or other restrictive disorders".)
Specimen collection — The optimal number, size, and location of lung biopsies depend upon the suspected diagnosis and the anatomic distribution of the disease process. The clinician should communicate to the thoracic surgeon any specific concerns and suggestions regarding these issues. HRCT imaging plays an essential role in selecting the best location(s) to biopsy [98,108]. (See "High resolution computed tomography of the lungs".)
●Involved, but not fibrotic areas – Regions that appear completely normal should be avoided, just as regions of greatest involvement and honeycombing should be avoided because biopsy from the latter sites generally reveals end stage fibrosis with little diagnostic value [109,110]. Lung parenchyma with mild involvement or lung parenchyma adjacent to obviously abnormal areas should be biopsied .
●Multilobar biopsies – Ideally, biopsies are obtained from more than one lobe of the lung and from areas of varying severity, as several studies suggest that this improves diagnostic accuracy [5,111]. In a retrospective study examining explanted lungs in 20 patients with UIP, areas resembling NSIP were seen in 16 of 20 explant specimens . In 28 of 109 (26 percent) patients with usual or nonspecific interstitial pneumonia, the histopathology in at least one lobe was discordant from another lobe (NSIP in one lobe and UIP in the other) . The outcomes in patients with NSIP-UIP discordant biopsy results were similar to patients with concordant UIP-UIP biopsy results, and significantly worse than patients with NSIP-NSIP concordant biopsy results [113,114]. This distinction, which has important prognostic and therapeutic implications, cannot be made without multiple biopsies from more than one lobe. In a separate series of 24 patients, the diagnostic yield was improved by multilobe biopsies in one-third . Among 15 patients with chronic hypersensitivity pneumonitis, sampling from more than one lobe helped to identify hypersensitivity pneumonitis in two patients who had chronic hypersensitivity pneumonitis on biopsies from one lobe and UIP on biopsies from another lobe .
●Lingular biopsy – Some of the older literature cautions against biopsy from the tip of the lingula but this has not been borne out in more recent studies because the diagnostic yield from lingular biopsies has been comparable to those from other lobes, and there is no reason to avoid the lingula if it is considered to be a good site based on the HRCT [5,98,109,116-118].
●Size of biopsy – In order to provide the pathologist with adequate tissue to evaluate the pattern and distribution of disease, lung biopsy samples are ideally greater than 4 cm in the greatest dimension when inflated and include a depth from the pleural surface of 3 to 5 cm .
Morbidity and mortality — Data on morbidity and mortality related to surgical lung biopsy for ILD vary widely depending on the source of the data, severity of respiratory impairment, type of lung disease, and age and sex of the patient. The largest analysis, of approximately 12,000 surgical lung biopsies, used a national database of a stratified sample of United States hospitals detailing diagnoses and procedure codes from 2000 to 2010 . In-hospital mortality was under 2 percent for elective procedures, which comprised two-thirds of the surgical lung biopsies for this period, and 16 percent for nonelective biopsies, which comprised the remaining one-third. Factors associated with an increased mortality were male sex, older age, comorbid conditions, thoracotomy, and a provisional diagnosis of idiopathic pulmonary fibrosis or rheumatic disease-related interstitial lung disease. (See 'When is lung biopsy unlikely to be helpful?' above.)
Individual case series report a wide variation in mortality following surgical lung biopsy [10,25,37,67,94,95,120,121]. The characteristics of the patient population appear to be the primary determinant of mortality in patients undergoing a surgical lung biopsy . An increasing number and severity of comorbidities, severe physiologic restriction, immunosuppressed state, underlying solid or hematologic malignancy, and respiratory failure are all associated with increased mortality. The case series reporting highest mortality post-surgical lung biopsy (13 to 70 percent) have a high proportion of patients with various combinations of these risk factors . However, even in series reporting a very high mortality, only a small proportion of deaths are directly attributed to the procedure itself by the authors. Series not including patients with these high risk factors report very low or no mortality . The following observations demonstrate the impact of these factors.
●Preoperative hypoxemia – The presence and degree of preoperative hypoxemia correlate with progressively worse outcomes in patients with ILD undergoing surgical lung biopsy. No mortality and little morbidity were noted in studies of ambulatory patients and those without significant hypoxemia [123-128].
•In a retrospective study of 48 patients undergoing surgical lung biopsy, the mortality was 4.2 percent for patients without hypoxemia, 6 percent for patients on supplemental oxygen, 60 percent for patients with severe hypoxemia and respiratory distress, and 75 percent for patients who were receiving invasive mechanical ventilation .
•In a study of 68 ambulatory patients with interstitial lung disease referred for a VATS lung biopsy, patients receiving supplemental oxygen were 21 times more likely to develop significant postoperative complications . In this study, an analysis of 22 previously published studies showed that patients with interstitial lung disease requiring preoperative mechanical ventilation were significantly more likely to die postoperatively when compared with patients who did not (47 versus 2 percent).
•In a study of 194 patients with ILD who underwent surgical lung biopsy, the mortality was 0 percent in patients without preoperative hypoxemia, 4.8 percent for patients without respiratory failure, and 100 percent for patients with ILD and preoperative respiratory failure .
●Acute exacerbation or rapid progression of ILD – Patients with an exacerbation or rapid progression of their ILD at the time of biopsy are at a particularly high risk of perioperative complications and death.
•In a series reporting outcomes in 60 patients with IPF undergoing surgical lung biopsy, 7 of the 10 IPF patients who died after a surgical lung biopsy were experiencing an acute exacerbation of IPF at the time of the biopsy .
•In a series of 200 patients with idiopathic ILDs undergoing surgical lung biopsy, patients experiencing an acute exacerbation were 10 times more likely to die after a surgical lung biopsy, than patients without an acute exacerbation (28.6 versus 3 percent mortality) .
•In a series of 76 patients with UIP, all four of the patients who died had diffuse alveolar damage superimposed on UIP .
However, these postoperative deaths need to be interpreted in the context that patients with IPF exacerbation have a very high mortality irrespective of whether not they undergo a surgical lung biopsy [54,56-62]. (See "Acute exacerbations of idiopathic pulmonary fibrosis".)
PROCESSING LUNG BIOPSY SPECIMENS — Lung biopsy specimens are sent for histopathologic analysis, accompanied by clinical information for the pathologist including the suspected diagnosis or differential diagnosis. If the patient is immunosuppressed or infection is suspected (eg, fever, short duration of symptoms), samples are sent for mycobacterial, fungal, and viral studies. Sending surgical biopsy specimens routinely for microbiologic testing is not necessary in patients with interstitial lung disease because culture results in this group of patients are rarely useful clinically [114,130].
Frozen sections are generally not useful in the diagnosis of diffuse parenchymal lung disease but may be used during surgical biopsy to assess whether an adequate sample has been obtained or when malignancy is suspected.
As the sample size is small, the entirety of transbronchial biopsy or transbronchial cryobiopsy specimens not sent to microbiology should be processed and examined. Surgical lung biopsy specimens are gently inflated by injection of formalin prior to sectioning to facilitate visualization of the interstitium [5,131]. Overinflation however must be avoided as this may cause loss of pathologic features, such as washing out macrophages from the alveolar spaces. For diffuse parenchymal lung disease, the routine initial stain is hematoxylin and eosin; additional staining to help assess the extent of fibrosis and elastosis (eg, elastic van Gieson) should also be considered.
Special stains are performed as indicated based on the clinical suspicion or initial findings. As examples, staining for CD1a is done when Langerhans cell histiocytosis is suspected, immunostaining for monoclonal populations may be indicated in specimens with a high proportion of lymphocytes, and special mycobacterial and fungal stains are done whenever granulomas are noted. Tissue can be stained with Congo red if amyloidosis is suspected clinically or based on radiologic or histopathologic appearance. Similarly, polarizing light is used to identify birefringent material when talcosis or pneumoconiosis is suspected. (See "Interpretation of lung biopsy results in interstitial lung disease", section on 'Langerhans cell granulomatosis'.)
Consultation with a pathologist familiar with the histopathological features of interstitial pneumonias and integration of clinical data in a multidisciplinary conference is highly recommended. The interpretation of lung biopsies obtained for diffuse parenchymal lung disease is discussed separately. (See "Interpretation of lung biopsy results in interstitial lung disease".)
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.)
●Beyond the Basics topics (see "Patient education: Flexible bronchoscopy (Beyond the Basics)")
SUMMARY AND RECOMMENDATIONS
●Diffuse parenchymal lung diseases, 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. An approach to evaluating immunocompetent adults with ILD is shown in the algorithm (algorithm 1) and discussed in detail separately. (See 'Introduction' above and "Approach to the adult with interstitial lung disease: Clinical evaluation" and "Approach to the adult with interstitial lung disease: Diagnostic testing".)
●Indications for lung biopsy in patients with ILD include atypical clinical features (age <50 years, fever, weight loss, hemoptysis, signs of vasculitis); a progressive course; a normal, atypical, or rapidly changing chest radiograph or high-resolution CT scan (HRCT); unexplained extrapulmonary manifestations; or pulmonary vascular disease of unclear origin. (See 'Overview' above.)
●Lung biopsy is less likely to be helpful in patients with a known systemic rheumatic (connective tissue) disease or with acute respiratory failure complicating ILD. (See 'When is lung biopsy unlikely to be helpful?' above.)
●Flexible bronchoscopy with transbronchial lung biopsy (TBLB) is minimally invasive and is often the biopsy procedure of choice when sarcoidosis, hypersensitivity pneumonitis, lymphangitic carcinomatosis, eosinophilic pneumonia, alveolar proteinosis, or infection is suspected. (See 'Transbronchial lung biopsy' above.)
●TBLB samples are a few millimeters in size and are likely to miss diseases that are patchy or require examination of a larger area of tissue for accurate diagnosis (eg, usual interstitial pneumonitis [UIP], nonspecific interstitial pneumonia [NSIP], vasculitis). (See 'What are the diagnostic limitations?' above.)
●Typically, four to six TBLBs are obtained from areas of lung that appear involved radiographically. If the lungs are uniformly involved, the lower lobe or both upper and lower lobes are biopsied. All biopsies are obtained on the same side to avoid the risk of bilateral pneumothoraces. (See 'Specimen collection and diagnostic yield' above.)
●Ancillary bronchoscopic tests such as endobronchial biopsy and bronchoalveolar lavage can help improve the diagnostic yield of TBLB. For patients with hilar or mediastinal adenopathy, endobronchial ultrasound guided transbronchial needle aspiration (EBUS-TBNA) may contribute to the diagnostic yield, although general anesthesia and specialized equipment are required. (See 'Ancillary tests' above and "Basic principles and technique of bronchoalveolar lavage" and "Role of bronchoalveolar lavage in diagnosis of interstitial lung disease".)
●Transbronchial cryobiopsy (cryo-TBB) is a bronchoscopic technique performed under moderate sedation or general anesthesia that is designed to obtain larger biopsy samples than TBLB. When performed in centers of expertise, Cryo-TBB may be an acceptable less invasive alternative to surgical lung biopsy (SLB) in patients with central, peribronchial, or diffuse interstitial processes based on improved safety and only modestly decreased diagnostic yield. (See 'Transbronchial cryobiopsy' above.)
●Surgical lung biopsy specimens can be obtained via video assisted thoracoscopic surgery (VATS) or thoracotomy; the choice between these procedures is typically determined by the expertise and preference of the thoracic surgeon. Thoracotomy may be preferred in the setting of severe pleural disease, a bleeding diathesis, or mechanical ventilation. (See 'VATS versus thoracotomy' above.)
●In order to provide the pathologist with adequate tissue to evaluate the pattern and distribution of disease, surgical biopsies should be greater than 4 cm in the greatest dimension when inflated and include a depth from the pleural surface of 3 to 5 cm. Ideally, specimens are obtained from more than one lobe of the lung. (See 'Specimen collection' above.)
●TBLB, cryo-TBB, and surgical lung biopsy specimens are sent for histopathologic analysis and, when indicated, mycobacterial, fungal, and viral testing. (See 'Processing lung biopsy specimens' above.)
●Consultation with a pathologist familiar with the histopathological features of interstitial pneumonias and integration of clinical and radiologic data in a multidisciplinary conference is highly recommended. The interpretation of lung biopsy results in the context of the clinical setting is discussed separately. (See "Interpretation of lung biopsy results in interstitial lung disease".)
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