- Email: [email protected]
Surgical Lung Biopsy for Interstitial Lung Diseases
[
Recent Advances in Chest Medicine
]
Surgical Lung Biopsy for Interstitial Lung Diseases Rishi Raj, MD; Kirtee Raparia, MD; David A. Lynch, MD; and Kevin K. Brown, MD
This review addresses common questions regarding the role of surgical lung biopsy (SLB) in the diagnosis and treatment of interstitial lung disease (ILD). We specifically address when a SLB can be diagnostic as well as when it may be avoided; for example, when the combination of the clinical context and the imaging pattern seen on high-resolution CT (HRCT) chest scans can provide a confident diagnosis. Existing studies on the diagnostic utility as well as the complications associated with SLB are reviewed; also reviewed are the performance characteristics and reliability of HRCT scans of the chest in predicting the underlying histopathologic findings of the lung. The review is formatted in the form of answers to questions that clinicians regularly ask when considering an SLB in a patient with ILD.
CHEST 2017; 151(5):1131-1140
idiopathic pulmonary fibrosis; interstitial lung disease; lung biopsy; pulmonary fibrosis; surgical lung biopsy
KEY WORDS:
‘‘Surgical operations are of two kinds: those that benefit the patient and those that kill him.’’1 Albucasis (940 to 1013)
Considerable progress has been made in our understanding of interstitial lung diseases (ILDs). Even in the rare disorders, we now have some understanding of their clinical presentations and natural history. Detailed information from a number of collaborating specialists is often required for diagnosis, as the use of a multidisciplinary team has been shown to significantly improve the accuracy as well as overall confidence in the final diagnosis.2,3 This process requires data generated from a number of commonly and generally sequentially performed investigations. A comprehensive clinical
ABBREVIATIONS: CTD = connective tissue disease; CTD-ILD = connective tissue disease–associated interstitial lung disease; HRCT = highresolution CT; IIP = idiopathic interstitial pneumonia; ILD = interstitial lung disease; IPF = idiopathic pulmonary fibrosis; NSIP = nonspecific interstitial pneumonia; SLB = surgical lung biopsy; TBBX = transbronchial biopsy; UIP = usual interstitial pneumonia AFFILIATIONS: From the Department of Pulmonary and Critical Care Medicine (Dr Raj) and the Department of Pathology (Dr Raparia), Northwestern University, Chicago, IL; and Department of Radiology
journal.publications.chestnet.org
evaluation performed by the pulmonary clinician defines the clinical context, whereas interpretation of the chest imaging is provided by the thoracic radiologist. When these investigations are inadequate to provide a confident diagnosis, the clinician must consider whether there is a role for bronchoscopy (including BAL and/or transbronchial biopsy [TBBX]) and/or surgical lung biopsy (SLB), as an SLB may provide diagnostic and prognostic information that cannot be obtained by using less invasive methods. The present review focuses on the role of SLB in this process, including when an SLB may be particularly useful and when it may not be necessary, the limitations of the pathologic
(Dr Lynch) and the Department of Pulmonary and Critical Care Medicine (Dr Brown), National Jewish Health, Denver, CO. CORRESPONDENCE TO: Rishi Raj, MD, Northwestern University, Pulmonary and Critical Care Medicine, 676 N St. Clair St, Ste 1400, Chicago, IL 60611; e-mail: [email protected] Copyright Ó 2016 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved. DOI: http://dx.doi.org/10.1016/j.chest.2016.06.019
1131
information obtained, and how the information can be incorporated with clinical context and chest imaging pattern to achieve either a confident or definitive diagnosis. The review takes the form of a series of questions, followed by a brief summary of the underlying relevant literature and recommendations based on this literature and expert opinion. Because all diagnostic and therapeutic decisions must be individualized, it should be recognized that these are general recommendations that cannot be directly applied to all patients.
When Can the Combination of the Clinical Context and Chest Imaging Pattern on HighResolution CT Scanning Provide a Confident Diagnosis? The importance of a comprehensive history and physical examination cannot be overemphasized, as these two items define the clinical context and generate the most important data in evaluating patients with ILD (Fig 1).4,5 Details of what constitutes a complete history, physical examination, and appropriate noninvasive diagnostic testing as it pertains to the evaluation of a patient with ILD are beyond the scope of this review and can be obtained elsewhere. However, the history, physical examination, and noninvasive testing should focus on the severity and temporal behavior of symptoms, the presence of preexisting systemic conditions known to be associated
with the development of ILD (particularly signs and symptoms of any extrapulmonary disease), the presence of a family history of lung disease, and the exposure to substances known to result in pulmonary injury. Pulmonary physiology complements the history and physical examination in providing a measure of impairment and in establishing a baseline against which to assess future disease activity or response to therapy. When available, the temporal behavior of the disease in terms of signs and symptoms, clinical variability, radiologic progression vs stability, and responsiveness to any previous intervention can all add important information. A high-resolution CT (HRCT) chest scan is the next investigation, and all patients with suspected ILD should undergo this procedure (Fig 1). For the test to provide useful information, careful attention to CT scanning techniques is critical.6 Appropriate technique will include contiguous thin sections and multiplanar reconstructions. Expiratory and prone images often provide important information and should be considered in all patients. In particular, the imaging technologists must ensure that inspiration is adequate and that respiratory motion is absent. Previous chest imaging, when available, should be reviewed and compared with more recent imaging to assess for evolution of the interstitial process. With these caveats, many ILDs are associated with HRCT patterns that
Clinical context + HRCT scan pattern For example: certain cases of IPF, CTD-ILD, and HP, etc
Diagnostic Not diagnostic Diagnostic Bronchoscopy, BAL, and biopsy (in selected cases)
Not diagnostic Diagnostic Surgical Lung Biopsy
Not diagnostic
Multidisciplinary discussion
Treat, follow-up, and revisit diagnosis as necessary Figure 1 – Suggested algorithm outlining the role of surgical lung biopsy in interstitial lung diseases. CTD-ILD ¼ connective tissue disease–associated interstitial lung disease; HP ¼ hypersensitivity pneumonitis; HRCT ¼ high-resolution CT; IPF ¼ idiopathic pulmonary fibrosis.
1132 Recent Advances in Chest Medicine
[
151#5 CHEST MAY 2017
]
significantly narrow the differential.7-10 However, there is a substantial learning curve associated with the interpretation of these images, and dedicated thoracic radiologists will have a lower interobserver variation than general radiologists.11 Similar to radiologists, clinicians’ performance—with or without the HRCT scanning information—varies with each individual’s experience and expertise.12 The pattern seen on HRCT scans of the chest provides critical information, can often predict the underlying histologic pattern, and is defined by the combination of the radiologic features and their distribution. A usual interstitial pneumonia (UIP) pattern is defined as peripheral and basal-predominant disease characterized by the presence of reticular abnormalities, honeycombing (clustered cystic airspaces of comparable diameters, characterized by well-defined walls, usually subpleural, and 3-10 mm in diameter), and the absence of a number of features such as extensive ground-glass abnormality, profuse micronodules, discrete cysts, diffuse mosaic attenuation or air trapping, and consolidation (Figs 2A, 2B).1 When a trained thoracic radiologist has a high level of confidence in the presence of a definite UIP pattern, the findings are specific (but not sensitive) for the presence of a histopathologic UIP pattern on the SLB (e-Tables 1, 2). When this pattern is seen in the clinical context of idiopathic interstitial pneumonia (IIP), these findings are diagnostic of idiopathic pulmonary fibrosis (IPF), and an SLB is not needed. For example, more than one-half of the patients enrolled in recent IPF clinical trials received a diagnosis based on the combination of the clinical context and HRCT pattern alone (e-Table 3). HRCT patterns other than “definite UIP pattern” (Figs 3A, 3B, 4A, 4B, 5A, 5B) are usually neither sensitive, nor
specific enough to preclude the need for an SLB when a definitive histopathologic pattern diagnosis is necessary (e-Table 2). An exception to this general rule may be made when the CT scan features are otherwise typical for UIP, but honeycombing is absent. In this situation, the predictive value for UIP is > 80%13 and may be regarded as diagnostic of histologic UIP in subjects with a high pretest clinical suspicion of IPF, particularly in those aged > 65 years in whom the pretest probability of IPF is already high.14 Common competing chest imaging patterns include nonspecific interstitial pneumonia (NSIP) and fibrotic forms of hypersensitivity pneumonitis, although patterns suggestive of sarcoidosis, and organizing pneumonia have all been described in patients with histologic UIP.15-17 A UIP pattern can be particularly hard to distinguish from NSIP; a significant proportion of HRCT scans with an NSIP imaging pattern will have a UIP histologic pattern.15,18-22 Distinguishing between NSIP and UIP patterns on HRCT scans is made even more difficult because, over time, the chest imaging pattern in a subgroup of patients with NSIP may evolve to suggest UIP.23,24 When studied under controlled conditions, the intraobserver and interobserver agreement on HRCT pattern can vary considerably, depending on the study design, experience and expertise of the interpreting radiologists, and the heterogeneity of the diagnoses in the patient population studied (e-Table 2). This subjectivity in the interpretation of the HRCT findings is important to recognize, especially in cases in which the HRCT pattern diagnosis is made with low confidence or if the HRCT findings are discordant with the clinical context. Because specific chest imaging patterns are often seen in particular clinical contexts, a number of disorders may sometimes be diagnosed with confidence without
Figure 2 – A, B, Usual interstitial pneumonitis pattern. (A) Axial and (B) coronal images through the chest show peripheral-predominant, basal-predominant reticular abnormality with small areas of honeycombing (arrows).
journal.publications.chestnet.org
1133
Figure 3 – A, B, Possible usual interstitial pneumonitis pattern. (A) Axial and (B) coronal images through the chest show peripheral-predominant, basal-predominant reticular abnormality without honeycombing. Biopsy revealed usual interstitial pneumonitis.
the need to obtain lung tissue. These disorders include connective tissue disease–associated ILD (CTD-ILD) and ILD that is temporally associated with a specific and clinically significant medication, environmental, occupational, avocational, or accidental exposure. An SLB is often unnecessary for many of these patients because diagnosis and treatment decisions are generally based on the combination of the clinical context, chest imaging pattern, degree of impairment, and rate of progression, rather than the findings on SLB.4,5 However, when the chest imaging pattern is atypical for the clinical context, or the longitudinal behavior of the disease differs substantially from what is expected, an SLB should be reconsidered.
When Can the Clinical Context and Chest Imaging Pattern on HRCT Be Combined With Bronchoscopy and TBBX to Provide a Confident Diagnosis? In the appropriate clinical context and with supportive findings from the HRCT scans, a TBBX can commonly
be used to make a diagnosis of sarcoidosis, berylliosis, pulmonary alveolar proteinosis, lymphangitic carcinomatosis, or lymphangioleiomyomatosis (HMB45-positive tissue).25,26 In a minority of patients with hypersensitivity pneumonitis, an appropriate clinical context and HRCT pattern can be combined with TBBX findings to make a confident diagnosis; however, the appropriate histologic findings are present only in a small proportion of patients.25,27 In the correct clinical context, histologic organizing pneumonia has a relatively distinct appearance on HRCT scans, and a TBBX with typical histopathologic findings can make a confident diagnosis of cryptogenic organizing pneumonia.25,28-30 BAL cell differential counts can be helpful in a minority of patients; an eosinophilia (> 25%) can be diagnostic of eosinophilic pneumonia, and a predominantly lymphocytic BAL, although not diagnostic of a specific disorder, points to diagnoses other than IPF.31 In all cases, if the longitudinal behavior of the patient’s disease differs from the course predicted by the original diagnosis, the need for an SLB should be reconsidered.25,28-30
Figure 4 – A, B, Atypical usual interstitial pneumonitis. (A) Axial and (B) coronal images through the chest in a patient with scleroderma show basalpredominant, reticular and ground-glass abnormality without honeycombing. There is slight peripheral predominance, but the extent of ground-glass abnormality is greater than would be expected for usual interstitial pneumonitis. However, biopsy revealed usual interstitial pneumonitis.
1134 Recent Advances in Chest Medicine
[
151#5 CHEST MAY 2017
]
Figure 5 – A, B, Hypersensitivity pneumonitis. (A) Axial and (B) coronal images through the chest show reticular and ground-glass abnormality, with slight midlung predominance and relative sparing of the lung bases. There is a small amount of posterior subpleural honeycombing on the axial image. Despite this finding, the distribution is inconsistent with usual interstitial pneumonitis and much more suggestive of hypersensitivity pneumonitis. Biopsy revealed hypersensitivity pneumonitis.
If the identification of histologic UIP is needed for a definitive diagnosis of IPF, tissue obtained by TBBX will be inadequate. TBBXs cannot be used to make a conclusive histopathologic diagnosis of UIP because the UIP histopathologic pattern depends on the identification of specific low-power microscopic findings such as areas of normal lung alternating with areas of patchy fibrosis and microscopic honeycombing. These changes can only be fully appreciated on an SLB (Figs 6A, 6B).32 Individual features that can be seen on TBBX such as fibroblast foci are not specific for UIP. Although in retrospective unblinded studies of patients with IPF, varying combinations of UIP histopathologic features (including fibroblast foci and honeycombing) have been shown in up to one-third33-35 of TBBXs, there are no prospective studies using an acceptable gold standard demonstrating that TBBXs can be confidently used to diagnose IPF.
The current IPF consensus statement is silent on the diagnostic fate of patients who do not have a UIP pattern on HRCT and cannot, or choose not to, undergo an SLB.2 In these patients, bronchoscopy may provide useful information, and the previous IPF statement offers guidance for assigning a probable diagnosis to these patients.36 Age and extent of fibrosis on imaging are predictive of IPF in patients aged > 65 years, even in the absence of honeycombing as long as there are no clinical or radiologic findings to suggest an alternative diagnosis.14
Should an SLB Be Performed in Patients With Acute Respiratory Failure and a Previously Undiagnosed ILD? Patients with previously undiagnosed ILD may present with acute respiratory failure. This group includes
Figure 6 – A, Usual interstitial pneumonia. A low-power view of the lung biopsy specimen shows temporally and spatially heterogeneous patchy (primarily subpleural) fibrosis with intervening areas of normal lung parenchyma. This geographic heterogeneity can only be appreciated in a lowpower view of a surgical lung biopsy specimen, not a transbronchial biopsy specimen. B, Usual interstitial pneumonia. A high-power view of the lung biopsy specimen shows temporal heterogeneity with areas of dense, remodeled lung showing microscopic honeycombing and abrupt transition to relatively normal alveolar lung parenchyma.
journal.publications.chestnet.org
1135
patients with previously unrecognized ILD presenting with an acute exacerbation, as well as patients with previously recognized ILD but in whom the evaluation was deferred due to patient or physician preference. The vast majority of SLB data in patients with respiratory failure come from patients with ARDS or those who were immunocompromised with pulmonary infiltrates (e-Table 4); infection and malignancy are the most common specific diagnoses in these series. Diffusely metastatic pulmonary malignancy can usually be diagnosed by using TBBX. BAL identifies the majority of pulmonary infections with high sensitivity and negative predictive value, and has performance characteristics comparable to that of SLB.37,38 The majority of noninfectious and nonmalignant diagnoses in these series are described by using nonspecific terms such as fibrosis, nonspecific pneumonitis, chronic pneumonitis, interstitial fibrosis, interstitial pneumonitis, and interstitial pulmonary fibrosis, etc, none of which provides a specific histologic pattern diagnosis. All fibrotic ILDs, including IPF, CTD-associated UIP or NSIP, idiopathic NSIP, chronic hypersensitivity pneumonitis, desquamative interstitial pneumonia, and asbestosis, have been associated with acute exacerbations and respiratory failure. Patients with acute exacerbations of fibrotic ILD generally exhibit diffuse alveolar damage or organizing pneumonia superimposed on an underlying fibrotic pattern, and this underlying fibrotic pattern can often be difficult or impossible to define because of the superimposed acute findings.39,40 In addition, it is unclear how results of an SLB alter therapeutic decision-making in these patients because they are often treated similarly regardless of biopsy findings and have a generally poor prognosis.39,41-46 Therefore, an SLB is generally not recommended in patients with a newly diagnosed fibrosing ILD who present in respiratory failure because the morbidity and mortality are relatively high, and the procedure only rarely provides clinically actionable information that cannot be obtained by other, less invasive means. Exceptions might include patients with an unusual clinical course or if the HRCT pattern suggests an unusual infection or malignancy such as lymphoma that cannot be diagnosed by any other means.
Should an SLB Be Performed in Patients With CTD-ILD? The ability of HRCT scans to predict the underlying histopathologic pattern is maintained in CTD. A UIP
1136 Recent Advances in Chest Medicine
chest imaging pattern on HRCT predicts the presence of a UIP histopathologic pattern in patients with rheumatoid arthritis associated–ILD with a high degree of specificity (96%) and positive predictive value (95%).47 The association between the underlying histopathologic pattern and clinical outcomes in patients with CTD is less certain than that seen in the IIPs. For example, in some studies, the UIP histopathologic pattern on SLB results is associated with a worse prognosis in patients with rheumatoid arthritis associated–ILD48,49 and scleroderma,50 but other studies concluded that the extent of disease on HRCT scanning is the primary driver of outcome.51-53 No difference in outcomes between NSIP and UIP was noted in a patient series with various CTDs.54 A recent model incorporating demographic and physiologic variables predicted prognosis in patients with fibrosing CTD-ILD without the need for biopsy (Gender-Age-Physiology [GAP] Index).55 In addition, there are no studies in patients with CTD-ILD that have used the histopathologic pattern to prospectively direct therapy. In a retrospective cohort study, the response to immunosuppressive therapy seemed similar across histologic subtypes.56 As a general rule, when the chest imaging pattern seen on HRCT is consistent with what would be expected in a specific CTD, an SLB sample does not provide additional prognostic information beyond that available from demographic, physiologic, chest imaging, and disease extent variables. However, when chest imaging features inconsistent with, or atypical for the underlying CTD are seen, or the longitudinal behavior of the disease differs from that expected, an SLB should be reconsidered.
What Are the Ideal Biopsy Site, Number, and Size? The preoperative HRCT chest scan should be used as a guide to the site of biopsy.5,57 A TBBX may be preferable to an SLB if most of the abnormality on the HRCT scan is centrally located, distant from the pleura. Regions of lung most intensely affected by fibrosis, particularly areas of honeycomb change, should generally be avoided because biopsy specimens from these sites often reveal end-stage fibrosis with only modest diagnostic value.58 The site of biopsy should be focused on involved lung parenchyma or areas adjacent to obviously abnormal lung.5 Older literature cautions against biopsy specimens from the lingula, but this caveat has not been borne out in more recent studies.57-59 Although not prospectively studied, a specimen size of at least 3 2 1 cm3 seems to be adequate.57 No fewer
[
151#5 CHEST MAY 2017
]
than two biopsy specimens from separate lobes should be obtained to address the possibility of discordant histopathologic findings (eg, explanted lungs in patients with UIP can exhibit areas of NSIP in up to 80% of cases).60 Prospective studies have documented an NSIP pattern in one lobe and a UIP pattern in the other lobe in approximately 25% of all UIP cases.61,62 Routinely sending surgical biopsy specimens from patients with ILD for microbiologic assessment and culture is generally not necessary,63 and this testing should be dictated by the specific clinical circumstances.
What Are the Complications and Who Is at Risk of Dying After an SLB? The average in-hospital mortality for patients undergoing SLB in the United States from 2000 to 2011 was 1.7% for elective procedures and 16% for nonelective procedures.64 Reported mortality after SLB in individual series (e-Fig 1, e-Table 4) varies from 0%65 to as high as 70%, and even in series with high mortality, the mortality was seldom attributed to the SLB procedure itself.66 Post-SLB mortality is best viewed as a number that varies by more than 100-fold depending on specific risk factors; the actual risk for an individual patient can therefore be substantially higher or lower than the average mortality rate.67 In general, patients with more severe disease and significant comorbidities are more likely to die after an SLB. Mortality seems higher in patients with hypoxemic respiratory failure, physiologically severe or rapidly progressive disease, clinically significant comorbidities, and malignancy, as well as in patients who are
immunosuppressed (e-Fig 1, e-Table 4). The series reporting no or low mortality differed from series reporting higher mortality in that they included few or no patients with severe hypoxia, poor functional status, severe physiologic restriction, rapidly progressive/ accelerated ILD, respiratory failure, malignancy, immunocompromise, or multisystem organ failure.67 Hypoxemic patients are at particular risk for complications, and the severity of hypoxia directly correlates with worse outcomes,68,69 with mortality increasing in tandem with progressively increasing hypoxia (one series reported a mortality of 4.2% for patients without hypoxemia, 6% for patients on supplemental oxygen, 60% for patients with severe hypoxia and respiratory distress, and 75% for patients who were receiving invasive mechanical ventilation70). Patients in respiratory failure are significantly more likely to die postoperatively than those without respiratory failure (47.3% vs 2.2% in one series,68 and 100% vs 4.8% in another69). Patients with rapidly progressive disease are also at high risk of death. Seventy percent of the patients who died after an SLB in one series had an acute exacerbation of IPF,44 and in another series patients with IIP and an acute exacerbation were 10 times as likely to die after an SLB compared with patients in stable condition (28.6% vs 3.0% mortality).71 The presence of significant pulmonary hypertension is also associated with poorer outcomes.68 Advanced age alone is not a contraindication to performing a biopsy; appropriately selected older patients have outcomes comparable to that of younger patients.72 Complications after an SLB include acute exacerbation of IPF or other underlying ILD, pneumothorax, persistent air leak, hemothorax, and ICU admission. As with mortality, there is a wide variation in the reported complication rate that seems to be correlated with the number and severity of comorbidities and the degree of physiologic restriction in patients undergoing the procedure (e-Table 4).
How Should the Data Obtained From an SLB Be Used in Forming a Final Diagnosis?
Figure 7 – Cellular nonspecific interstitial pneumonia. The lung biopsy shows diffuse and relatively uniform chronic inflammatory infiltrate (primarily composed of lymphocytes and plasma cells) involving the alveolar walls.
journal.publications.chestnet.org
The histopathologic pattern obtained from an SLB must be combined with the clinical context and the chest imaging pattern seen on HRCT to provide a final diagnosis (Figs 6, 7, 8, 9). The histologic data have a significant influence on the final consensus diagnosis in ILD,3 especially when the combination of the clinical context and chest imaging data produce an uncertain diagnosis, and when the final diagnosis is not IPF.3,73 There is increasing awareness that a substantial
1137
this subjectivity is important to recognize in cases in which the findings are discordant with clinical and chest imaging data. Diagnostic confidence, the proportion of correct diagnoses, and agreement on the final diagnosis progressively increase as clinicians, radiologists, and pathologists share and discuss the available clinical, radiologic, and histopathologic data and reach a best-fit consensus diagnosis; the agreement on the final diagnosis is thus significantly better than when histopathologic information is interpreted in isolation.3 This multidisciplinary approach is now considered to be the gold standard and is the recommended standard of care for the diagnosis of ILDs.2 Figure 8 – Fibrotic nonspecific interstitial pneumonia. The lung biopsy shows mild to moderate fibrosis with preservation of the lung architecture and without microscopic honeycombing and heterogeneity.
proportion of subjects who have histologic UIP have CT appearances that would be regarded as “inconsistent” with UIP.74 Such discordance of CT scanning and histologic findings should always prompt careful review, as well as a renewed search for alternative diagnoses such as hypersensitivity pneumonitis. However, the histopathologic pattern seen on the SLB does not, in itself, provide a final diagnosis. The same histopathologic pattern can be seen in a variety of ILDs, whereas some ILDs can present with more than one histopathologic pattern. For example, CTD-associated ILD, hypersensitivity pneumonitis, and drug-induced ILD can all present with a variety of histopathologic patterns, including diffuse alveolar damage, organizing pneumonia, NSIP, or UIP patterns.75 There is also an element of subjectivity when it comes to interpreting histopathologic findings (e-Table 5), and
Comparisons of SLB specimens with explanted lungs have shown that up to 10% of surgical specimens can be nondiagnostic despite being technically adequate.60 Prospective studies have shown that a histopathologic diagnosis can be uncertain in up to 18% of ILD cases.76 Furthermore, a definitive pathologic pattern diagnosis is not always possible despite a technically adequate SLB sample and a multidisciplinary discussion because of conflicting clinical, radiologic, or histopathologic findings that cannot be reconciled; reported prevalence of uncertain diagnosis varies from 2% to 20% in various series.3,73,77,78 For these patients, it is reasonable to provide a best-fit working diagnosis. Factors to consider include degree of physiologic limitation, predominant radiologic pattern (eg, ground-glass vs fibrotic) and its extent, predominant histopathologic pattern (eg, cellular vs fibrotic), clinical behavior, and response to empiric treatment (if appropriate).79 These patients should be followed up closely, monitoring the longitudinal behavior of the disease with the intent of revising the diagnosis if the clinical course or response to therapy is incongruent with the working diagnosis.
Conclusions
Figure 9 – Organizing pneumonia. The lung biopsy shows dense aggregates of loose fibroblasts within terminal airways and adjacent alveolar spaces, accompanied by inflammatory interstitial infiltrate.
1138 Recent Advances in Chest Medicine
When confronted with a patient with suspected ILD, the combination of the clinical context and chest imaging pattern on HRCT scans may provide a confident diagnosis without the need for additional evaluation. The addition of BAL and TBBX to the clinical and imaging data can be diagnostic in a subset of other patients. In appropriately selected patients, an SLB provides valuable diagnostic information that cannot be obtained by any other means with low risk of complication. However, an SLB is unnecessary when a confident UIP chest imaging pattern is seen on HRCT scanning in the clinical context of an IIP, nor is it
[
151#5 CHEST MAY 2017
]
routinely regularly needed in patients with a welldefined CTD-ILD and those with a specific, clinically significant, and temporally appropriate drug, occupational, avocational, or accidental exposure. SLBs are generally unhelpful in patients with acute respiratory failure and a new diagnosis of fibrosing ILD. Severe hypoxia, respiratory failure, immunocompromised status, and rapidly progressive disease prior to biopsy are associated with increased morbidity and mortality. Multidisciplinary discussion, using the available clinical, HRCT, and SLB data, is useful in making a definitive diagnosis; however, diagnostic uncertainty may still occur in a minority of patients with ILD.
13. Chung JH, Chawla A, Peljto AL, et al. CT scan findings of probable usual interstitial pneumonitis have a high predictive value for histologic usual interstitial pneumonitis. Chest. 2015;147(2):450-459.
Acknowledgments
19. Thomeer M, Demedts M, Behr J, et al. Multidisciplinary interobserver agreement in the diagnosis of idiopathic pulmonary fibrosis. Eur Respir J. 2008;31(3):585-591.
Author contributions: R. R. takes responsibility for the content of the manuscript. R. R., K. R., D. A. L., and K. K. B. contributed to creating the manuscript outline, literature review, writing the manuscript, creating/providing the figures associated with the manuscript, and revising the manuscript. Financial/nonfinancial disclosures: None declared. Other contributions: The authors thank Kenneth Nugent, MD, for his thoughtful and constructive review and critique of the manuscript. Additional information: The e-Figure and e-Tables can be found in the Supplemental Materials section of the online article.
14. Fell CD, Martinez FJ, Liu LX, et al. Clinical predictors of a diagnosis of idiopathic pulmonary fibrosis. Am J Respir Crit Care Med. 2010;181(8):832-837. 15. Sverzellati N, Wells AU, Tomassetti S, et al. Biopsy-proved idiopathic pulmonary fibrosis: spectrum of nondiagnostic thinsection CT diagnoses. Radiology. 2010;254(3):957-964. 16. Aziz ZA, Wells AU, Hansell DM, et al. HRCT diagnosis of diffuse parenchymal lung disease: inter-observer variation. Thorax. 2004;59(6):506-511. 17. Padley SP, Padhani AR, Nicholson A, Hansell DM. Pulmonary sarcoidosis mimicking cryptogenic fibrosing alveolitis on CT. Clinical Radiol. 1996;51(11):807-810. 18. Flaherty KR, Thwaite EL, Kazerooni EA, et al. Radiological versus histological diagnosis in UIP and NSIP: survival implications. Thorax. 2003;58(2):143-148.
20. MacDonald SL, Rubens MB, Hansell DM, et al. Nonspecific interstitial pneumonia and usual interstitial pneumonia: comparative appearances at and diagnostic accuracy of thin-section CT. Radiology. 2001;221(3):600-605. 21. Elliot TL, Lynch DA, Newell JD Jr, et al. High-resolution computed tomography features of nonspecific interstitial pneumonia and usual interstitial pneumonia. J Comput Assist Tomogr. 2005;29(3):339-345. 22. Hartman TE, Swensen SJ, Hansell DM, et al. Nonspecific interstitial pneumonia: variable appearance at high-resolution chest CT. Radiology. 2000;217(3):701-705.
1. Bishop WJ. The Early History of Surgery. NY: Barnes & Noble; 1995.
23. Silva CI, Muller NL, Hansell DM, Lee KS, Nicholson AG, Wells AU. Nonspecific interstitial pneumonia and idiopathic pulmonary fibrosis: changes in pattern and distribution of disease over time. Radiology. 2008;247(1):251-259.
2. Raghu G, Collard HR, Egan JJ, et al. An official ATS/ERS/JRS/ALAT statement: idiopathic pulmonary fibrosis: evidence-based guidelines for diagnosis and management. Am J Respir Crit Care Med. 2011;183(6):788-824.
24. Lee HY, Lee KS, Jeong YJ, et al. High-resolution CT findings in fibrotic idiopathic interstitial pneumonias with little honeycombing: serial changes and prognostic implications. AJR Am J Roentgenol. 2012;199(5):982-989.
3. Flaherty KR, King TE Jr, Raghu G, et al. Idiopathic interstitial pneumonia: what is the effect of a multidisciplinary approach to diagnosis? Am J Respir Crit Care Med. 2004;170(8):904-910.
25. Glaspole IN, Wells AU, du Bois RM. Lung biopsy in diffuse parenchymal lung disease. Monaldi Arch Chest Dis. 2001;56(3):225-232.
References
4. Raghu G, Brown KK. Interstitial lung disease: clinical evaluation and keys to an accurate diagnosis. Clin Chest Med. 2004;25(3):409-419, v.
26. Bonetti F, Chiodera PL, Pea M, et al. Transbronchial biopsy in lymphangiomyomatosis of the lung. HMB45 for diagnosis. Am J Surg Pathol. 1993;17(11):1092-1102.
5. Raghu G. Interstitial lung disease: a diagnostic approach. Are CT scan and lung biopsy indicated in every patient? Am J Respir Crit Care Med. 1995;151(3 pt 1):909-914.
27. Lacasse Y, Fraser RS, Fournier M, Cormier Y. Diagnostic accuracy of transbronchial biopsy in acute farmer’s lung disease. Chest. 1997;112(6):1459-1465.
6. Mayo JR. CT evaluation of diffuse infiltrative lung disease: dose considerations and optimal technique. J Thorac Imaging. 2009;24(4): 252-259.
28. Poletti V, Cazzato S, Minicuci N, Zompatori M, Burzi M, Schiattone ML. The diagnostic value of bronchoalveolar lavage and transbronchial lung biopsy in cryptogenic organizing pneumonia. Eur Respir J. 1996;9(12):2513-2516.
7. Lynch DA. Lung disease related to collagen vascular disease. J Thorac Imaging. 2009;24(4):299-309. 8. Silva CI, Churg A, Muller NL. Hypersensitivity pneumonitis: spectrum of high-resolution CT and pathologic findings. AJR Am J Roentgenol. 2007;188(2):334-344. 9. Lynch DA, Huckleberry JM. Usual interstitial pneumonia: typical and atypical high-resolution computed tomography features. Semin Ultrasound CT MR. 2014;35(1):12-23. 10. Lynch DA, Travis WD, Muller NL, et al. Idiopathic interstitial pneumonias: CT features. Radiology. 2005;236(1):10-21. 11. Flaherty KR, Andrei AC, King TE Jr, et al. Idiopathic interstitial pneumonia: do community and academic physicians agree on diagnosis? Am J Respir Crit Care Med. 2007;175(10): 1054-1060. 12. Raghu G, Mageto YN, Lockhart D, Schmidt RA, Wood DE, Godwin JD. The accuracy of the clinical diagnosis of new-onset idiopathic pulmonary fibrosis and other interstitial lung disease: a prospective study. Chest. 1999;116(5):1168-1174.
journal.publications.chestnet.org
29. Dina R, Sheppard MN. The histological diagnosis of clinically documented cases of cryptogenic organizing pneumonia: diagnostic features in transbronchial biopsies. Histopathology. 1993;23(6):541-545. 30. Cordier JF. Organising pneumonia. Thorax. 2000;55(4):318-328. 31. Meyer KC, Raghu G, Baughman RP, et al. An official American Thoracic Society clinical practice guideline: the clinical utility of bronchoalveolar lavage cellular analysis in interstitial lung disease. Am J Respir Crit Care Med. 2012;185(9):1004-1014. 32. Churg A, Schwarz M. Transbronchial biopsy and usual interstitial pneumonia: a new paradigm? Chest. 2006;129(5):1117-1118. 33. Berbescu EA, Katzenstein AL, Snow JL, Zisman DA. Transbronchial biopsy in usual interstitial pneumonia. Chest. 2006;129(5):1126-1131. 34. Tomassetti S, Cavazza A, Colby TV, et al. Transbronchial biopsy is useful in predicting UIP pattern. Respir Res. 2012;13:96. 35. Shim HS, Park MS, Park IK. Histopathologic findings of transbronchial biopsy in usual interstitial pneumonia. Pathol Int. 2010;60(5):373-377.
1139
36. American Thoracic Society. Idiopathic pulmonary fibrosis: diagnosis and treatment. International consensus statement. American Thoracic Society (ATS), and the European Respiratory Society (ERS). Am J Respir Crit Care Med. 2000;161(2 pt 1):646-664. 37. Springmeyer SC, Hackman RC, Holle R, et al. Use of bronchoalveolar lavage to diagnose acute diffuse pneumonia in the immunocompromised host. J Infect Dis. 1986;154(4):604-610. 38. Gaussorgues P, Piperno D, Bachmann P, et al. Comparison of nonbronchoscopic bronchoalveolar lavage to open lung biopsy for the bacteriologic diagnosis of pulmonary infections in mechanically ventilated patients. Intensive Care Med. 1989;15(2):94-98.
58. Gaensler EA, Carrington CB. Open biopsy for chronic diffuse infiltrative lung disease: clinical, roentgenographic, and physiological correlations in 502 patients. Ann Thorac Surg. 1980;30(5):411-426. 59. Miller RR, Nelems B, Muller NL, Evans KG, Ostrow DN. Lingular and right middle lobe biopsy in the assessment of diffuse lung disease. Ann Thorac Surg. 1987;44(3):269-273. 60. Katzenstein AL, Zisman DA, Litzky LA, Nguyen BT, Kotloff RM. Usual interstitial pneumonia: histologic study of biopsy and explant specimens. Am J Surg Pathol. 2002;26(12):1567-1577.
39. Churg A, Wright JL, Tazelaar HD. Acute exacerbations of fibrotic interstitial lung disease. Histopathology. 2011;58(4):525-530.
61. Monaghan H, Wells AU, Colby TV, du Bois RM, Hansell DM, Nicholson AG. Prognostic implications of histologic patterns in multiple surgical lung biopsies from patients with idiopathic interstitial pneumonias. Chest. 2004;125(2):522-526.
40. Churg A, Muller NL, Silva CI, Wright JL. Acute exacerbation (acute lung injury of unknown cause) in UIP and other forms of fibrotic interstitial pneumonias. Am J Surg Pathol. 2007;31(2):277-284.
62. Flaherty KR, Travis WD, Colby TV, et al. Histopathologic variability in usual and nonspecific interstitial pneumonias. Am J Respir Crit Care Med. 2001;164(9):1722-1727.
41. Collard HR, Moore BB, Flaherty KR, et al. Acute exacerbations of idiopathic pulmonary fibrosis. Am J Respir Crit Care Med. 2007;176(7):636-643.
63. Fibla JJ, Brunelli A, Allen MS, et al. Microbiology specimens obtained at the time of surgical lung biopsy for interstitial lung disease: clinical yield and cost analysis. Eur J Cardiothorac Surg. 2012;41(1):36-38.
42. Ryerson CJ, Collard HR. Acute exacerbations complicating interstitial lung disease. Curr Opin Pulm Med. 2014;20(5):436-441. 43. Parambil JG, Myers JL, Ryu JH. Histopathologic features and outcome of patients with acute exacerbation of idiopathic pulmonary fibrosis undergoing surgical lung biopsy. Chest. 2005;128(5):3310-3315.
64. Hutchinson JP, Fogarty AW, McKeever TM, Hubbard RB. Inhospital mortality after surgical lung biopsy for interstitial lung disease in the United States. 2000 to 2011. Am J Respir Crit Care Med. 2016;193(10):1161-1167.
44. Utz JP, Ryu JH, Douglas WW, et al. High short-term mortality following lung biopsy for usual interstitial pneumonia. Eur Respir J. 2001;17(2):175-179.
65. Fibla JJ, Molins L, Blanco A, et al. Video-assisted thoracoscopic lung biopsy in the diagnosis of interstitial lung disease: a prospective, multicenter study in 224 patients. Arch Bronconeumol. 2012;48(3):81-85.
45. Blivet S, Philit F, Sab JM, et al. Outcome of patients with idiopathic pulmonary fibrosis admitted to the ICU for respiratory failure. Chest. 2001;120(1):209-212.
66. Warner DO, Warner MA, Divertie MB. Open lung biopsy in patients with diffuse pulmonary infiltrates and acute respiratory failure. Am Rev Respir Dis. 1988;137(1):90-94.
46. Fumeaux T, Rothmeier C, Jolliet P. Outcome of mechanical ventilation for acute respiratory failure in patients with pulmonary fibrosis. Intensive Care Med. 2001;27(12):1868-1874.
67. Raj R, Brown KK. Mortality related to surgical lung biopsy in patients with interstitial lung disease. The devil is in the denominator. Am J Respir Crit Care Med. 2016;193(10):1082-1084.
47. Assayag D, Elicker BM, Urbania TH, et al. Rheumatoid arthritisassociated interstitial lung disease: radiologic identification of usual interstitial pneumonia pattern. Radiology. 2014;270(2):583-588.
68. Kreider ME, Hansen-Flaschen J, Ahmad NN, et al. Complications of video-assisted thoracoscopic lung biopsy in patients with interstitial lung disease. Ann Thorac Surg. 2007;83(3):1140-1144.
48. Assayag D, Lubin M, Lee JS, King TE, Collard HR, Ryerson CJ. Predictors of mortality in rheumatoid arthritis-related interstitial lung disease. Respirology. 2014;19(4):493-500.
69. Kayatta MO, Ahmed S, Hammel JA, et al. Surgical biopsy of suspected interstitial lung disease is superior to radiographic diagnosis. Ann Thorac Surg. 2013;96(2):399-401.
49. Nakamura Y, Suda T, Kaida Y, et al. Rheumatoid lung disease: prognostic analysis of 54 biopsy-proven cases. Respir Med. 2012;106(8):1164-1169.
70. LoCicero J 3rd. Does every patient with enigmatic lung disease deserve a lung biopsy? The continuing dilemma. Chest. 1994;106(3):706-708.
50. Fischer A, Swigris JJ, Groshong SD, et al. Clinically significant interstitial lung disease in limited scleroderma: histopathology, clinical features, and survival. Chest. 2008;134(3):601-605. 51. Bouros D, Wells AU, Nicholson AG, et al. Histopathologic subsets of fibrosing alveolitis in patients with systemic sclerosis and their relationship to outcome. Am J Respir Crit Care Med. 2002;165(12): 1581-1586. 52. Moore OA, Goh N, Corte T, et al. Extent of disease on highresolution computed tomography lung is a predictor of decline and mortality in systemic sclerosis-related interstitial lung disease. Rheumatology. 2013;52(1):155-160. 53. Winstone TA, Assayag D, Wilcox PG, et al. Predictors of mortality and progression in scleroderma-associated interstitial lung disease: a systematic review. Chest. 2014;146(2):422-436.
71. Park JH, Kim DK, Kim DS, et al. Mortality and risk factors for surgical lung biopsy in patients with idiopathic interstitial pneumonia. Eur J Cardiothorac Surg. 2007;31(6):1115-1119. 72. Jaklitsch MT, DeCamp MM Jr, Liptay MJ, et al. Video-assisted thoracic surgery in the elderly. A review of 307 cases. Chest. 1996;110(3):751-758. 73. Hunninghake GW, Zimmerman MB, Schwartz DA, et al. Utility of a lung biopsy for the diagnosis of idiopathic pulmonary fibrosis. Am J Respir Crit Care Med. 2001;164(2):193-196. 74. Yagihashi K, Huckleberry J, Colby TV, et al. Radiologic-pathologic discordance in biopsy-proven usual interstitial pneumonia. Eur Respir J. 2016;47(4):1189-1197. 75. Leslie KO. Pulmonary pathology for the clinician. Clin Chest Med. 2006;27(1 suppl 1):S1-S10, v.
54. Park JH, Kim DS, Park IN, et al. Prognosis of fibrotic interstitial pneumonia: idiopathic versus collagen vascular disease-related subtypes. Am J Respir Crit Care Med. 2007;175(7):705-711.
76. Nicholson AG, Addis BJ, Bharucha H, et al. Inter-observer variation between pathologists in diffuse parenchymal lung disease. Thorax. 2004;59(6):500-505.
55. Ryerson CJ, Vittinghoff E, Ley B, et al. Predicting survival across chronic interstitial lung disease: the ILD-GAP model. Chest. 2014;145(4):723-728.
77. Ryerson CJ, Urbania TH, Richeldi L, et al. Prevalence and prognosis of unclassifiable interstitial lung disease. Eur Respir J. 2013;42(3): 750-757.
56. Fischer A, Brown KK, Du Bois RM, et al. Mycophenolate mofetil improves lung function in connective tissue disease-associated interstitial lung disease. J Rheumatol. 2013;40(5):640-646.
78. Troy L, Glaspole I, Goh N, et al. Prevalence and prognosis of unclassifiable interstitial lung disease. Eur Respir J. 2014;43(5): 1529-1530.
57. Qureshi RA, Ahmed TA, Grayson AD, Soorae AS, Drakeley MJ, Page RD. Does lung biopsy help patients with interstitial lung disease? Eur J Cardiothorac Surg. 2002;21(4):621-626; discussion 626.
79. Cottin V, Wells A. Unclassified or unclassifiable interstitial lung disease: confusing or helpful disease category? Eur Respir J. 2013;42(3):576-579.
1140 Recent Advances in Chest Medicine
[
151#5 CHEST MAY 2017
]
Recent Advances in Chest Medicine
]
Surgical Lung Biopsy for Interstitial Lung Diseases Rishi Raj, MD; Kirtee Raparia, MD; David A. Lynch, MD; and Kevin K. Brown, MD
This review addresses common questions regarding the role of surgical lung biopsy (SLB) in the diagnosis and treatment of interstitial lung disease (ILD). We specifically address when a SLB can be diagnostic as well as when it may be avoided; for example, when the combination of the clinical context and the imaging pattern seen on high-resolution CT (HRCT) chest scans can provide a confident diagnosis. Existing studies on the diagnostic utility as well as the complications associated with SLB are reviewed; also reviewed are the performance characteristics and reliability of HRCT scans of the chest in predicting the underlying histopathologic findings of the lung. The review is formatted in the form of answers to questions that clinicians regularly ask when considering an SLB in a patient with ILD.
CHEST 2017; 151(5):1131-1140
idiopathic pulmonary fibrosis; interstitial lung disease; lung biopsy; pulmonary fibrosis; surgical lung biopsy
KEY WORDS:
‘‘Surgical operations are of two kinds: those that benefit the patient and those that kill him.’’1 Albucasis (940 to 1013)
Considerable progress has been made in our understanding of interstitial lung diseases (ILDs). Even in the rare disorders, we now have some understanding of their clinical presentations and natural history. Detailed information from a number of collaborating specialists is often required for diagnosis, as the use of a multidisciplinary team has been shown to significantly improve the accuracy as well as overall confidence in the final diagnosis.2,3 This process requires data generated from a number of commonly and generally sequentially performed investigations. A comprehensive clinical
ABBREVIATIONS: CTD = connective tissue disease; CTD-ILD = connective tissue disease–associated interstitial lung disease; HRCT = highresolution CT; IIP = idiopathic interstitial pneumonia; ILD = interstitial lung disease; IPF = idiopathic pulmonary fibrosis; NSIP = nonspecific interstitial pneumonia; SLB = surgical lung biopsy; TBBX = transbronchial biopsy; UIP = usual interstitial pneumonia AFFILIATIONS: From the Department of Pulmonary and Critical Care Medicine (Dr Raj) and the Department of Pathology (Dr Raparia), Northwestern University, Chicago, IL; and Department of Radiology
journal.publications.chestnet.org
evaluation performed by the pulmonary clinician defines the clinical context, whereas interpretation of the chest imaging is provided by the thoracic radiologist. When these investigations are inadequate to provide a confident diagnosis, the clinician must consider whether there is a role for bronchoscopy (including BAL and/or transbronchial biopsy [TBBX]) and/or surgical lung biopsy (SLB), as an SLB may provide diagnostic and prognostic information that cannot be obtained by using less invasive methods. The present review focuses on the role of SLB in this process, including when an SLB may be particularly useful and when it may not be necessary, the limitations of the pathologic
(Dr Lynch) and the Department of Pulmonary and Critical Care Medicine (Dr Brown), National Jewish Health, Denver, CO. CORRESPONDENCE TO: Rishi Raj, MD, Northwestern University, Pulmonary and Critical Care Medicine, 676 N St. Clair St, Ste 1400, Chicago, IL 60611; e-mail: [email protected] Copyright Ó 2016 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved. DOI: http://dx.doi.org/10.1016/j.chest.2016.06.019
1131
information obtained, and how the information can be incorporated with clinical context and chest imaging pattern to achieve either a confident or definitive diagnosis. The review takes the form of a series of questions, followed by a brief summary of the underlying relevant literature and recommendations based on this literature and expert opinion. Because all diagnostic and therapeutic decisions must be individualized, it should be recognized that these are general recommendations that cannot be directly applied to all patients.
When Can the Combination of the Clinical Context and Chest Imaging Pattern on HighResolution CT Scanning Provide a Confident Diagnosis? The importance of a comprehensive history and physical examination cannot be overemphasized, as these two items define the clinical context and generate the most important data in evaluating patients with ILD (Fig 1).4,5 Details of what constitutes a complete history, physical examination, and appropriate noninvasive diagnostic testing as it pertains to the evaluation of a patient with ILD are beyond the scope of this review and can be obtained elsewhere. However, the history, physical examination, and noninvasive testing should focus on the severity and temporal behavior of symptoms, the presence of preexisting systemic conditions known to be associated
with the development of ILD (particularly signs and symptoms of any extrapulmonary disease), the presence of a family history of lung disease, and the exposure to substances known to result in pulmonary injury. Pulmonary physiology complements the history and physical examination in providing a measure of impairment and in establishing a baseline against which to assess future disease activity or response to therapy. When available, the temporal behavior of the disease in terms of signs and symptoms, clinical variability, radiologic progression vs stability, and responsiveness to any previous intervention can all add important information. A high-resolution CT (HRCT) chest scan is the next investigation, and all patients with suspected ILD should undergo this procedure (Fig 1). For the test to provide useful information, careful attention to CT scanning techniques is critical.6 Appropriate technique will include contiguous thin sections and multiplanar reconstructions. Expiratory and prone images often provide important information and should be considered in all patients. In particular, the imaging technologists must ensure that inspiration is adequate and that respiratory motion is absent. Previous chest imaging, when available, should be reviewed and compared with more recent imaging to assess for evolution of the interstitial process. With these caveats, many ILDs are associated with HRCT patterns that
Clinical context + HRCT scan pattern For example: certain cases of IPF, CTD-ILD, and HP, etc
Diagnostic Not diagnostic Diagnostic Bronchoscopy, BAL, and biopsy (in selected cases)
Not diagnostic Diagnostic Surgical Lung Biopsy
Not diagnostic
Multidisciplinary discussion
Treat, follow-up, and revisit diagnosis as necessary Figure 1 – Suggested algorithm outlining the role of surgical lung biopsy in interstitial lung diseases. CTD-ILD ¼ connective tissue disease–associated interstitial lung disease; HP ¼ hypersensitivity pneumonitis; HRCT ¼ high-resolution CT; IPF ¼ idiopathic pulmonary fibrosis.
1132 Recent Advances in Chest Medicine
[
151#5 CHEST MAY 2017
]
significantly narrow the differential.7-10 However, there is a substantial learning curve associated with the interpretation of these images, and dedicated thoracic radiologists will have a lower interobserver variation than general radiologists.11 Similar to radiologists, clinicians’ performance—with or without the HRCT scanning information—varies with each individual’s experience and expertise.12 The pattern seen on HRCT scans of the chest provides critical information, can often predict the underlying histologic pattern, and is defined by the combination of the radiologic features and their distribution. A usual interstitial pneumonia (UIP) pattern is defined as peripheral and basal-predominant disease characterized by the presence of reticular abnormalities, honeycombing (clustered cystic airspaces of comparable diameters, characterized by well-defined walls, usually subpleural, and 3-10 mm in diameter), and the absence of a number of features such as extensive ground-glass abnormality, profuse micronodules, discrete cysts, diffuse mosaic attenuation or air trapping, and consolidation (Figs 2A, 2B).1 When a trained thoracic radiologist has a high level of confidence in the presence of a definite UIP pattern, the findings are specific (but not sensitive) for the presence of a histopathologic UIP pattern on the SLB (e-Tables 1, 2). When this pattern is seen in the clinical context of idiopathic interstitial pneumonia (IIP), these findings are diagnostic of idiopathic pulmonary fibrosis (IPF), and an SLB is not needed. For example, more than one-half of the patients enrolled in recent IPF clinical trials received a diagnosis based on the combination of the clinical context and HRCT pattern alone (e-Table 3). HRCT patterns other than “definite UIP pattern” (Figs 3A, 3B, 4A, 4B, 5A, 5B) are usually neither sensitive, nor
specific enough to preclude the need for an SLB when a definitive histopathologic pattern diagnosis is necessary (e-Table 2). An exception to this general rule may be made when the CT scan features are otherwise typical for UIP, but honeycombing is absent. In this situation, the predictive value for UIP is > 80%13 and may be regarded as diagnostic of histologic UIP in subjects with a high pretest clinical suspicion of IPF, particularly in those aged > 65 years in whom the pretest probability of IPF is already high.14 Common competing chest imaging patterns include nonspecific interstitial pneumonia (NSIP) and fibrotic forms of hypersensitivity pneumonitis, although patterns suggestive of sarcoidosis, and organizing pneumonia have all been described in patients with histologic UIP.15-17 A UIP pattern can be particularly hard to distinguish from NSIP; a significant proportion of HRCT scans with an NSIP imaging pattern will have a UIP histologic pattern.15,18-22 Distinguishing between NSIP and UIP patterns on HRCT scans is made even more difficult because, over time, the chest imaging pattern in a subgroup of patients with NSIP may evolve to suggest UIP.23,24 When studied under controlled conditions, the intraobserver and interobserver agreement on HRCT pattern can vary considerably, depending on the study design, experience and expertise of the interpreting radiologists, and the heterogeneity of the diagnoses in the patient population studied (e-Table 2). This subjectivity in the interpretation of the HRCT findings is important to recognize, especially in cases in which the HRCT pattern diagnosis is made with low confidence or if the HRCT findings are discordant with the clinical context. Because specific chest imaging patterns are often seen in particular clinical contexts, a number of disorders may sometimes be diagnosed with confidence without
Figure 2 – A, B, Usual interstitial pneumonitis pattern. (A) Axial and (B) coronal images through the chest show peripheral-predominant, basal-predominant reticular abnormality with small areas of honeycombing (arrows).
journal.publications.chestnet.org
1133
Figure 3 – A, B, Possible usual interstitial pneumonitis pattern. (A) Axial and (B) coronal images through the chest show peripheral-predominant, basal-predominant reticular abnormality without honeycombing. Biopsy revealed usual interstitial pneumonitis.
the need to obtain lung tissue. These disorders include connective tissue disease–associated ILD (CTD-ILD) and ILD that is temporally associated with a specific and clinically significant medication, environmental, occupational, avocational, or accidental exposure. An SLB is often unnecessary for many of these patients because diagnosis and treatment decisions are generally based on the combination of the clinical context, chest imaging pattern, degree of impairment, and rate of progression, rather than the findings on SLB.4,5 However, when the chest imaging pattern is atypical for the clinical context, or the longitudinal behavior of the disease differs substantially from what is expected, an SLB should be reconsidered.
When Can the Clinical Context and Chest Imaging Pattern on HRCT Be Combined With Bronchoscopy and TBBX to Provide a Confident Diagnosis? In the appropriate clinical context and with supportive findings from the HRCT scans, a TBBX can commonly
be used to make a diagnosis of sarcoidosis, berylliosis, pulmonary alveolar proteinosis, lymphangitic carcinomatosis, or lymphangioleiomyomatosis (HMB45-positive tissue).25,26 In a minority of patients with hypersensitivity pneumonitis, an appropriate clinical context and HRCT pattern can be combined with TBBX findings to make a confident diagnosis; however, the appropriate histologic findings are present only in a small proportion of patients.25,27 In the correct clinical context, histologic organizing pneumonia has a relatively distinct appearance on HRCT scans, and a TBBX with typical histopathologic findings can make a confident diagnosis of cryptogenic organizing pneumonia.25,28-30 BAL cell differential counts can be helpful in a minority of patients; an eosinophilia (> 25%) can be diagnostic of eosinophilic pneumonia, and a predominantly lymphocytic BAL, although not diagnostic of a specific disorder, points to diagnoses other than IPF.31 In all cases, if the longitudinal behavior of the patient’s disease differs from the course predicted by the original diagnosis, the need for an SLB should be reconsidered.25,28-30
Figure 4 – A, B, Atypical usual interstitial pneumonitis. (A) Axial and (B) coronal images through the chest in a patient with scleroderma show basalpredominant, reticular and ground-glass abnormality without honeycombing. There is slight peripheral predominance, but the extent of ground-glass abnormality is greater than would be expected for usual interstitial pneumonitis. However, biopsy revealed usual interstitial pneumonitis.
1134 Recent Advances in Chest Medicine
[
151#5 CHEST MAY 2017
]
Figure 5 – A, B, Hypersensitivity pneumonitis. (A) Axial and (B) coronal images through the chest show reticular and ground-glass abnormality, with slight midlung predominance and relative sparing of the lung bases. There is a small amount of posterior subpleural honeycombing on the axial image. Despite this finding, the distribution is inconsistent with usual interstitial pneumonitis and much more suggestive of hypersensitivity pneumonitis. Biopsy revealed hypersensitivity pneumonitis.
If the identification of histologic UIP is needed for a definitive diagnosis of IPF, tissue obtained by TBBX will be inadequate. TBBXs cannot be used to make a conclusive histopathologic diagnosis of UIP because the UIP histopathologic pattern depends on the identification of specific low-power microscopic findings such as areas of normal lung alternating with areas of patchy fibrosis and microscopic honeycombing. These changes can only be fully appreciated on an SLB (Figs 6A, 6B).32 Individual features that can be seen on TBBX such as fibroblast foci are not specific for UIP. Although in retrospective unblinded studies of patients with IPF, varying combinations of UIP histopathologic features (including fibroblast foci and honeycombing) have been shown in up to one-third33-35 of TBBXs, there are no prospective studies using an acceptable gold standard demonstrating that TBBXs can be confidently used to diagnose IPF.
The current IPF consensus statement is silent on the diagnostic fate of patients who do not have a UIP pattern on HRCT and cannot, or choose not to, undergo an SLB.2 In these patients, bronchoscopy may provide useful information, and the previous IPF statement offers guidance for assigning a probable diagnosis to these patients.36 Age and extent of fibrosis on imaging are predictive of IPF in patients aged > 65 years, even in the absence of honeycombing as long as there are no clinical or radiologic findings to suggest an alternative diagnosis.14
Should an SLB Be Performed in Patients With Acute Respiratory Failure and a Previously Undiagnosed ILD? Patients with previously undiagnosed ILD may present with acute respiratory failure. This group includes
Figure 6 – A, Usual interstitial pneumonia. A low-power view of the lung biopsy specimen shows temporally and spatially heterogeneous patchy (primarily subpleural) fibrosis with intervening areas of normal lung parenchyma. This geographic heterogeneity can only be appreciated in a lowpower view of a surgical lung biopsy specimen, not a transbronchial biopsy specimen. B, Usual interstitial pneumonia. A high-power view of the lung biopsy specimen shows temporal heterogeneity with areas of dense, remodeled lung showing microscopic honeycombing and abrupt transition to relatively normal alveolar lung parenchyma.
journal.publications.chestnet.org
1135
patients with previously unrecognized ILD presenting with an acute exacerbation, as well as patients with previously recognized ILD but in whom the evaluation was deferred due to patient or physician preference. The vast majority of SLB data in patients with respiratory failure come from patients with ARDS or those who were immunocompromised with pulmonary infiltrates (e-Table 4); infection and malignancy are the most common specific diagnoses in these series. Diffusely metastatic pulmonary malignancy can usually be diagnosed by using TBBX. BAL identifies the majority of pulmonary infections with high sensitivity and negative predictive value, and has performance characteristics comparable to that of SLB.37,38 The majority of noninfectious and nonmalignant diagnoses in these series are described by using nonspecific terms such as fibrosis, nonspecific pneumonitis, chronic pneumonitis, interstitial fibrosis, interstitial pneumonitis, and interstitial pulmonary fibrosis, etc, none of which provides a specific histologic pattern diagnosis. All fibrotic ILDs, including IPF, CTD-associated UIP or NSIP, idiopathic NSIP, chronic hypersensitivity pneumonitis, desquamative interstitial pneumonia, and asbestosis, have been associated with acute exacerbations and respiratory failure. Patients with acute exacerbations of fibrotic ILD generally exhibit diffuse alveolar damage or organizing pneumonia superimposed on an underlying fibrotic pattern, and this underlying fibrotic pattern can often be difficult or impossible to define because of the superimposed acute findings.39,40 In addition, it is unclear how results of an SLB alter therapeutic decision-making in these patients because they are often treated similarly regardless of biopsy findings and have a generally poor prognosis.39,41-46 Therefore, an SLB is generally not recommended in patients with a newly diagnosed fibrosing ILD who present in respiratory failure because the morbidity and mortality are relatively high, and the procedure only rarely provides clinically actionable information that cannot be obtained by other, less invasive means. Exceptions might include patients with an unusual clinical course or if the HRCT pattern suggests an unusual infection or malignancy such as lymphoma that cannot be diagnosed by any other means.
Should an SLB Be Performed in Patients With CTD-ILD? The ability of HRCT scans to predict the underlying histopathologic pattern is maintained in CTD. A UIP
1136 Recent Advances in Chest Medicine
chest imaging pattern on HRCT predicts the presence of a UIP histopathologic pattern in patients with rheumatoid arthritis associated–ILD with a high degree of specificity (96%) and positive predictive value (95%).47 The association between the underlying histopathologic pattern and clinical outcomes in patients with CTD is less certain than that seen in the IIPs. For example, in some studies, the UIP histopathologic pattern on SLB results is associated with a worse prognosis in patients with rheumatoid arthritis associated–ILD48,49 and scleroderma,50 but other studies concluded that the extent of disease on HRCT scanning is the primary driver of outcome.51-53 No difference in outcomes between NSIP and UIP was noted in a patient series with various CTDs.54 A recent model incorporating demographic and physiologic variables predicted prognosis in patients with fibrosing CTD-ILD without the need for biopsy (Gender-Age-Physiology [GAP] Index).55 In addition, there are no studies in patients with CTD-ILD that have used the histopathologic pattern to prospectively direct therapy. In a retrospective cohort study, the response to immunosuppressive therapy seemed similar across histologic subtypes.56 As a general rule, when the chest imaging pattern seen on HRCT is consistent with what would be expected in a specific CTD, an SLB sample does not provide additional prognostic information beyond that available from demographic, physiologic, chest imaging, and disease extent variables. However, when chest imaging features inconsistent with, or atypical for the underlying CTD are seen, or the longitudinal behavior of the disease differs from that expected, an SLB should be reconsidered.
What Are the Ideal Biopsy Site, Number, and Size? The preoperative HRCT chest scan should be used as a guide to the site of biopsy.5,57 A TBBX may be preferable to an SLB if most of the abnormality on the HRCT scan is centrally located, distant from the pleura. Regions of lung most intensely affected by fibrosis, particularly areas of honeycomb change, should generally be avoided because biopsy specimens from these sites often reveal end-stage fibrosis with only modest diagnostic value.58 The site of biopsy should be focused on involved lung parenchyma or areas adjacent to obviously abnormal lung.5 Older literature cautions against biopsy specimens from the lingula, but this caveat has not been borne out in more recent studies.57-59 Although not prospectively studied, a specimen size of at least 3 2 1 cm3 seems to be adequate.57 No fewer
[
151#5 CHEST MAY 2017
]
than two biopsy specimens from separate lobes should be obtained to address the possibility of discordant histopathologic findings (eg, explanted lungs in patients with UIP can exhibit areas of NSIP in up to 80% of cases).60 Prospective studies have documented an NSIP pattern in one lobe and a UIP pattern in the other lobe in approximately 25% of all UIP cases.61,62 Routinely sending surgical biopsy specimens from patients with ILD for microbiologic assessment and culture is generally not necessary,63 and this testing should be dictated by the specific clinical circumstances.
What Are the Complications and Who Is at Risk of Dying After an SLB? The average in-hospital mortality for patients undergoing SLB in the United States from 2000 to 2011 was 1.7% for elective procedures and 16% for nonelective procedures.64 Reported mortality after SLB in individual series (e-Fig 1, e-Table 4) varies from 0%65 to as high as 70%, and even in series with high mortality, the mortality was seldom attributed to the SLB procedure itself.66 Post-SLB mortality is best viewed as a number that varies by more than 100-fold depending on specific risk factors; the actual risk for an individual patient can therefore be substantially higher or lower than the average mortality rate.67 In general, patients with more severe disease and significant comorbidities are more likely to die after an SLB. Mortality seems higher in patients with hypoxemic respiratory failure, physiologically severe or rapidly progressive disease, clinically significant comorbidities, and malignancy, as well as in patients who are
immunosuppressed (e-Fig 1, e-Table 4). The series reporting no or low mortality differed from series reporting higher mortality in that they included few or no patients with severe hypoxia, poor functional status, severe physiologic restriction, rapidly progressive/ accelerated ILD, respiratory failure, malignancy, immunocompromise, or multisystem organ failure.67 Hypoxemic patients are at particular risk for complications, and the severity of hypoxia directly correlates with worse outcomes,68,69 with mortality increasing in tandem with progressively increasing hypoxia (one series reported a mortality of 4.2% for patients without hypoxemia, 6% for patients on supplemental oxygen, 60% for patients with severe hypoxia and respiratory distress, and 75% for patients who were receiving invasive mechanical ventilation70). Patients in respiratory failure are significantly more likely to die postoperatively than those without respiratory failure (47.3% vs 2.2% in one series,68 and 100% vs 4.8% in another69). Patients with rapidly progressive disease are also at high risk of death. Seventy percent of the patients who died after an SLB in one series had an acute exacerbation of IPF,44 and in another series patients with IIP and an acute exacerbation were 10 times as likely to die after an SLB compared with patients in stable condition (28.6% vs 3.0% mortality).71 The presence of significant pulmonary hypertension is also associated with poorer outcomes.68 Advanced age alone is not a contraindication to performing a biopsy; appropriately selected older patients have outcomes comparable to that of younger patients.72 Complications after an SLB include acute exacerbation of IPF or other underlying ILD, pneumothorax, persistent air leak, hemothorax, and ICU admission. As with mortality, there is a wide variation in the reported complication rate that seems to be correlated with the number and severity of comorbidities and the degree of physiologic restriction in patients undergoing the procedure (e-Table 4).
How Should the Data Obtained From an SLB Be Used in Forming a Final Diagnosis?
Figure 7 – Cellular nonspecific interstitial pneumonia. The lung biopsy shows diffuse and relatively uniform chronic inflammatory infiltrate (primarily composed of lymphocytes and plasma cells) involving the alveolar walls.
journal.publications.chestnet.org
The histopathologic pattern obtained from an SLB must be combined with the clinical context and the chest imaging pattern seen on HRCT to provide a final diagnosis (Figs 6, 7, 8, 9). The histologic data have a significant influence on the final consensus diagnosis in ILD,3 especially when the combination of the clinical context and chest imaging data produce an uncertain diagnosis, and when the final diagnosis is not IPF.3,73 There is increasing awareness that a substantial
1137
this subjectivity is important to recognize in cases in which the findings are discordant with clinical and chest imaging data. Diagnostic confidence, the proportion of correct diagnoses, and agreement on the final diagnosis progressively increase as clinicians, radiologists, and pathologists share and discuss the available clinical, radiologic, and histopathologic data and reach a best-fit consensus diagnosis; the agreement on the final diagnosis is thus significantly better than when histopathologic information is interpreted in isolation.3 This multidisciplinary approach is now considered to be the gold standard and is the recommended standard of care for the diagnosis of ILDs.2 Figure 8 – Fibrotic nonspecific interstitial pneumonia. The lung biopsy shows mild to moderate fibrosis with preservation of the lung architecture and without microscopic honeycombing and heterogeneity.
proportion of subjects who have histologic UIP have CT appearances that would be regarded as “inconsistent” with UIP.74 Such discordance of CT scanning and histologic findings should always prompt careful review, as well as a renewed search for alternative diagnoses such as hypersensitivity pneumonitis. However, the histopathologic pattern seen on the SLB does not, in itself, provide a final diagnosis. The same histopathologic pattern can be seen in a variety of ILDs, whereas some ILDs can present with more than one histopathologic pattern. For example, CTD-associated ILD, hypersensitivity pneumonitis, and drug-induced ILD can all present with a variety of histopathologic patterns, including diffuse alveolar damage, organizing pneumonia, NSIP, or UIP patterns.75 There is also an element of subjectivity when it comes to interpreting histopathologic findings (e-Table 5), and
Comparisons of SLB specimens with explanted lungs have shown that up to 10% of surgical specimens can be nondiagnostic despite being technically adequate.60 Prospective studies have shown that a histopathologic diagnosis can be uncertain in up to 18% of ILD cases.76 Furthermore, a definitive pathologic pattern diagnosis is not always possible despite a technically adequate SLB sample and a multidisciplinary discussion because of conflicting clinical, radiologic, or histopathologic findings that cannot be reconciled; reported prevalence of uncertain diagnosis varies from 2% to 20% in various series.3,73,77,78 For these patients, it is reasonable to provide a best-fit working diagnosis. Factors to consider include degree of physiologic limitation, predominant radiologic pattern (eg, ground-glass vs fibrotic) and its extent, predominant histopathologic pattern (eg, cellular vs fibrotic), clinical behavior, and response to empiric treatment (if appropriate).79 These patients should be followed up closely, monitoring the longitudinal behavior of the disease with the intent of revising the diagnosis if the clinical course or response to therapy is incongruent with the working diagnosis.
Conclusions
Figure 9 – Organizing pneumonia. The lung biopsy shows dense aggregates of loose fibroblasts within terminal airways and adjacent alveolar spaces, accompanied by inflammatory interstitial infiltrate.
1138 Recent Advances in Chest Medicine
When confronted with a patient with suspected ILD, the combination of the clinical context and chest imaging pattern on HRCT scans may provide a confident diagnosis without the need for additional evaluation. The addition of BAL and TBBX to the clinical and imaging data can be diagnostic in a subset of other patients. In appropriately selected patients, an SLB provides valuable diagnostic information that cannot be obtained by any other means with low risk of complication. However, an SLB is unnecessary when a confident UIP chest imaging pattern is seen on HRCT scanning in the clinical context of an IIP, nor is it
[
151#5 CHEST MAY 2017
]
routinely regularly needed in patients with a welldefined CTD-ILD and those with a specific, clinically significant, and temporally appropriate drug, occupational, avocational, or accidental exposure. SLBs are generally unhelpful in patients with acute respiratory failure and a new diagnosis of fibrosing ILD. Severe hypoxia, respiratory failure, immunocompromised status, and rapidly progressive disease prior to biopsy are associated with increased morbidity and mortality. Multidisciplinary discussion, using the available clinical, HRCT, and SLB data, is useful in making a definitive diagnosis; however, diagnostic uncertainty may still occur in a minority of patients with ILD.
13. Chung JH, Chawla A, Peljto AL, et al. CT scan findings of probable usual interstitial pneumonitis have a high predictive value for histologic usual interstitial pneumonitis. Chest. 2015;147(2):450-459.
Acknowledgments
19. Thomeer M, Demedts M, Behr J, et al. Multidisciplinary interobserver agreement in the diagnosis of idiopathic pulmonary fibrosis. Eur Respir J. 2008;31(3):585-591.
Author contributions: R. R. takes responsibility for the content of the manuscript. R. R., K. R., D. A. L., and K. K. B. contributed to creating the manuscript outline, literature review, writing the manuscript, creating/providing the figures associated with the manuscript, and revising the manuscript. Financial/nonfinancial disclosures: None declared. Other contributions: The authors thank Kenneth Nugent, MD, for his thoughtful and constructive review and critique of the manuscript. Additional information: The e-Figure and e-Tables can be found in the Supplemental Materials section of the online article.
14. Fell CD, Martinez FJ, Liu LX, et al. Clinical predictors of a diagnosis of idiopathic pulmonary fibrosis. Am J Respir Crit Care Med. 2010;181(8):832-837. 15. Sverzellati N, Wells AU, Tomassetti S, et al. Biopsy-proved idiopathic pulmonary fibrosis: spectrum of nondiagnostic thinsection CT diagnoses. Radiology. 2010;254(3):957-964. 16. Aziz ZA, Wells AU, Hansell DM, et al. HRCT diagnosis of diffuse parenchymal lung disease: inter-observer variation. Thorax. 2004;59(6):506-511. 17. Padley SP, Padhani AR, Nicholson A, Hansell DM. Pulmonary sarcoidosis mimicking cryptogenic fibrosing alveolitis on CT. Clinical Radiol. 1996;51(11):807-810. 18. Flaherty KR, Thwaite EL, Kazerooni EA, et al. Radiological versus histological diagnosis in UIP and NSIP: survival implications. Thorax. 2003;58(2):143-148.
20. MacDonald SL, Rubens MB, Hansell DM, et al. Nonspecific interstitial pneumonia and usual interstitial pneumonia: comparative appearances at and diagnostic accuracy of thin-section CT. Radiology. 2001;221(3):600-605. 21. Elliot TL, Lynch DA, Newell JD Jr, et al. High-resolution computed tomography features of nonspecific interstitial pneumonia and usual interstitial pneumonia. J Comput Assist Tomogr. 2005;29(3):339-345. 22. Hartman TE, Swensen SJ, Hansell DM, et al. Nonspecific interstitial pneumonia: variable appearance at high-resolution chest CT. Radiology. 2000;217(3):701-705.
1. Bishop WJ. The Early History of Surgery. NY: Barnes & Noble; 1995.
23. Silva CI, Muller NL, Hansell DM, Lee KS, Nicholson AG, Wells AU. Nonspecific interstitial pneumonia and idiopathic pulmonary fibrosis: changes in pattern and distribution of disease over time. Radiology. 2008;247(1):251-259.
2. Raghu G, Collard HR, Egan JJ, et al. An official ATS/ERS/JRS/ALAT statement: idiopathic pulmonary fibrosis: evidence-based guidelines for diagnosis and management. Am J Respir Crit Care Med. 2011;183(6):788-824.
24. Lee HY, Lee KS, Jeong YJ, et al. High-resolution CT findings in fibrotic idiopathic interstitial pneumonias with little honeycombing: serial changes and prognostic implications. AJR Am J Roentgenol. 2012;199(5):982-989.
3. Flaherty KR, King TE Jr, Raghu G, et al. Idiopathic interstitial pneumonia: what is the effect of a multidisciplinary approach to diagnosis? Am J Respir Crit Care Med. 2004;170(8):904-910.
25. Glaspole IN, Wells AU, du Bois RM. Lung biopsy in diffuse parenchymal lung disease. Monaldi Arch Chest Dis. 2001;56(3):225-232.
References
4. Raghu G, Brown KK. Interstitial lung disease: clinical evaluation and keys to an accurate diagnosis. Clin Chest Med. 2004;25(3):409-419, v.
26. Bonetti F, Chiodera PL, Pea M, et al. Transbronchial biopsy in lymphangiomyomatosis of the lung. HMB45 for diagnosis. Am J Surg Pathol. 1993;17(11):1092-1102.
5. Raghu G. Interstitial lung disease: a diagnostic approach. Are CT scan and lung biopsy indicated in every patient? Am J Respir Crit Care Med. 1995;151(3 pt 1):909-914.
27. Lacasse Y, Fraser RS, Fournier M, Cormier Y. Diagnostic accuracy of transbronchial biopsy in acute farmer’s lung disease. Chest. 1997;112(6):1459-1465.
6. Mayo JR. CT evaluation of diffuse infiltrative lung disease: dose considerations and optimal technique. J Thorac Imaging. 2009;24(4): 252-259.
28. Poletti V, Cazzato S, Minicuci N, Zompatori M, Burzi M, Schiattone ML. The diagnostic value of bronchoalveolar lavage and transbronchial lung biopsy in cryptogenic organizing pneumonia. Eur Respir J. 1996;9(12):2513-2516.
7. Lynch DA. Lung disease related to collagen vascular disease. J Thorac Imaging. 2009;24(4):299-309. 8. Silva CI, Churg A, Muller NL. Hypersensitivity pneumonitis: spectrum of high-resolution CT and pathologic findings. AJR Am J Roentgenol. 2007;188(2):334-344. 9. Lynch DA, Huckleberry JM. Usual interstitial pneumonia: typical and atypical high-resolution computed tomography features. Semin Ultrasound CT MR. 2014;35(1):12-23. 10. Lynch DA, Travis WD, Muller NL, et al. Idiopathic interstitial pneumonias: CT features. Radiology. 2005;236(1):10-21. 11. Flaherty KR, Andrei AC, King TE Jr, et al. Idiopathic interstitial pneumonia: do community and academic physicians agree on diagnosis? Am J Respir Crit Care Med. 2007;175(10): 1054-1060. 12. Raghu G, Mageto YN, Lockhart D, Schmidt RA, Wood DE, Godwin JD. The accuracy of the clinical diagnosis of new-onset idiopathic pulmonary fibrosis and other interstitial lung disease: a prospective study. Chest. 1999;116(5):1168-1174.
journal.publications.chestnet.org
29. Dina R, Sheppard MN. The histological diagnosis of clinically documented cases of cryptogenic organizing pneumonia: diagnostic features in transbronchial biopsies. Histopathology. 1993;23(6):541-545. 30. Cordier JF. Organising pneumonia. Thorax. 2000;55(4):318-328. 31. Meyer KC, Raghu G, Baughman RP, et al. An official American Thoracic Society clinical practice guideline: the clinical utility of bronchoalveolar lavage cellular analysis in interstitial lung disease. Am J Respir Crit Care Med. 2012;185(9):1004-1014. 32. Churg A, Schwarz M. Transbronchial biopsy and usual interstitial pneumonia: a new paradigm? Chest. 2006;129(5):1117-1118. 33. Berbescu EA, Katzenstein AL, Snow JL, Zisman DA. Transbronchial biopsy in usual interstitial pneumonia. Chest. 2006;129(5):1126-1131. 34. Tomassetti S, Cavazza A, Colby TV, et al. Transbronchial biopsy is useful in predicting UIP pattern. Respir Res. 2012;13:96. 35. Shim HS, Park MS, Park IK. Histopathologic findings of transbronchial biopsy in usual interstitial pneumonia. Pathol Int. 2010;60(5):373-377.
1139
36. American Thoracic Society. Idiopathic pulmonary fibrosis: diagnosis and treatment. International consensus statement. American Thoracic Society (ATS), and the European Respiratory Society (ERS). Am J Respir Crit Care Med. 2000;161(2 pt 1):646-664. 37. Springmeyer SC, Hackman RC, Holle R, et al. Use of bronchoalveolar lavage to diagnose acute diffuse pneumonia in the immunocompromised host. J Infect Dis. 1986;154(4):604-610. 38. Gaussorgues P, Piperno D, Bachmann P, et al. Comparison of nonbronchoscopic bronchoalveolar lavage to open lung biopsy for the bacteriologic diagnosis of pulmonary infections in mechanically ventilated patients. Intensive Care Med. 1989;15(2):94-98.
58. Gaensler EA, Carrington CB. Open biopsy for chronic diffuse infiltrative lung disease: clinical, roentgenographic, and physiological correlations in 502 patients. Ann Thorac Surg. 1980;30(5):411-426. 59. Miller RR, Nelems B, Muller NL, Evans KG, Ostrow DN. Lingular and right middle lobe biopsy in the assessment of diffuse lung disease. Ann Thorac Surg. 1987;44(3):269-273. 60. Katzenstein AL, Zisman DA, Litzky LA, Nguyen BT, Kotloff RM. Usual interstitial pneumonia: histologic study of biopsy and explant specimens. Am J Surg Pathol. 2002;26(12):1567-1577.
39. Churg A, Wright JL, Tazelaar HD. Acute exacerbations of fibrotic interstitial lung disease. Histopathology. 2011;58(4):525-530.
61. Monaghan H, Wells AU, Colby TV, du Bois RM, Hansell DM, Nicholson AG. Prognostic implications of histologic patterns in multiple surgical lung biopsies from patients with idiopathic interstitial pneumonias. Chest. 2004;125(2):522-526.
40. Churg A, Muller NL, Silva CI, Wright JL. Acute exacerbation (acute lung injury of unknown cause) in UIP and other forms of fibrotic interstitial pneumonias. Am J Surg Pathol. 2007;31(2):277-284.
62. Flaherty KR, Travis WD, Colby TV, et al. Histopathologic variability in usual and nonspecific interstitial pneumonias. Am J Respir Crit Care Med. 2001;164(9):1722-1727.
41. Collard HR, Moore BB, Flaherty KR, et al. Acute exacerbations of idiopathic pulmonary fibrosis. Am J Respir Crit Care Med. 2007;176(7):636-643.
63. Fibla JJ, Brunelli A, Allen MS, et al. Microbiology specimens obtained at the time of surgical lung biopsy for interstitial lung disease: clinical yield and cost analysis. Eur J Cardiothorac Surg. 2012;41(1):36-38.
42. Ryerson CJ, Collard HR. Acute exacerbations complicating interstitial lung disease. Curr Opin Pulm Med. 2014;20(5):436-441. 43. Parambil JG, Myers JL, Ryu JH. Histopathologic features and outcome of patients with acute exacerbation of idiopathic pulmonary fibrosis undergoing surgical lung biopsy. Chest. 2005;128(5):3310-3315.
64. Hutchinson JP, Fogarty AW, McKeever TM, Hubbard RB. Inhospital mortality after surgical lung biopsy for interstitial lung disease in the United States. 2000 to 2011. Am J Respir Crit Care Med. 2016;193(10):1161-1167.
44. Utz JP, Ryu JH, Douglas WW, et al. High short-term mortality following lung biopsy for usual interstitial pneumonia. Eur Respir J. 2001;17(2):175-179.
65. Fibla JJ, Molins L, Blanco A, et al. Video-assisted thoracoscopic lung biopsy in the diagnosis of interstitial lung disease: a prospective, multicenter study in 224 patients. Arch Bronconeumol. 2012;48(3):81-85.
45. Blivet S, Philit F, Sab JM, et al. Outcome of patients with idiopathic pulmonary fibrosis admitted to the ICU for respiratory failure. Chest. 2001;120(1):209-212.
66. Warner DO, Warner MA, Divertie MB. Open lung biopsy in patients with diffuse pulmonary infiltrates and acute respiratory failure. Am Rev Respir Dis. 1988;137(1):90-94.
46. Fumeaux T, Rothmeier C, Jolliet P. Outcome of mechanical ventilation for acute respiratory failure in patients with pulmonary fibrosis. Intensive Care Med. 2001;27(12):1868-1874.
67. Raj R, Brown KK. Mortality related to surgical lung biopsy in patients with interstitial lung disease. The devil is in the denominator. Am J Respir Crit Care Med. 2016;193(10):1082-1084.
47. Assayag D, Elicker BM, Urbania TH, et al. Rheumatoid arthritisassociated interstitial lung disease: radiologic identification of usual interstitial pneumonia pattern. Radiology. 2014;270(2):583-588.
68. Kreider ME, Hansen-Flaschen J, Ahmad NN, et al. Complications of video-assisted thoracoscopic lung biopsy in patients with interstitial lung disease. Ann Thorac Surg. 2007;83(3):1140-1144.
48. Assayag D, Lubin M, Lee JS, King TE, Collard HR, Ryerson CJ. Predictors of mortality in rheumatoid arthritis-related interstitial lung disease. Respirology. 2014;19(4):493-500.
69. Kayatta MO, Ahmed S, Hammel JA, et al. Surgical biopsy of suspected interstitial lung disease is superior to radiographic diagnosis. Ann Thorac Surg. 2013;96(2):399-401.
49. Nakamura Y, Suda T, Kaida Y, et al. Rheumatoid lung disease: prognostic analysis of 54 biopsy-proven cases. Respir Med. 2012;106(8):1164-1169.
70. LoCicero J 3rd. Does every patient with enigmatic lung disease deserve a lung biopsy? The continuing dilemma. Chest. 1994;106(3):706-708.
50. Fischer A, Swigris JJ, Groshong SD, et al. Clinically significant interstitial lung disease in limited scleroderma: histopathology, clinical features, and survival. Chest. 2008;134(3):601-605. 51. Bouros D, Wells AU, Nicholson AG, et al. Histopathologic subsets of fibrosing alveolitis in patients with systemic sclerosis and their relationship to outcome. Am J Respir Crit Care Med. 2002;165(12): 1581-1586. 52. Moore OA, Goh N, Corte T, et al. Extent of disease on highresolution computed tomography lung is a predictor of decline and mortality in systemic sclerosis-related interstitial lung disease. Rheumatology. 2013;52(1):155-160. 53. Winstone TA, Assayag D, Wilcox PG, et al. Predictors of mortality and progression in scleroderma-associated interstitial lung disease: a systematic review. Chest. 2014;146(2):422-436.
71. Park JH, Kim DK, Kim DS, et al. Mortality and risk factors for surgical lung biopsy in patients with idiopathic interstitial pneumonia. Eur J Cardiothorac Surg. 2007;31(6):1115-1119. 72. Jaklitsch MT, DeCamp MM Jr, Liptay MJ, et al. Video-assisted thoracic surgery in the elderly. A review of 307 cases. Chest. 1996;110(3):751-758. 73. Hunninghake GW, Zimmerman MB, Schwartz DA, et al. Utility of a lung biopsy for the diagnosis of idiopathic pulmonary fibrosis. Am J Respir Crit Care Med. 2001;164(2):193-196. 74. Yagihashi K, Huckleberry J, Colby TV, et al. Radiologic-pathologic discordance in biopsy-proven usual interstitial pneumonia. Eur Respir J. 2016;47(4):1189-1197. 75. Leslie KO. Pulmonary pathology for the clinician. Clin Chest Med. 2006;27(1 suppl 1):S1-S10, v.
54. Park JH, Kim DS, Park IN, et al. Prognosis of fibrotic interstitial pneumonia: idiopathic versus collagen vascular disease-related subtypes. Am J Respir Crit Care Med. 2007;175(7):705-711.
76. Nicholson AG, Addis BJ, Bharucha H, et al. Inter-observer variation between pathologists in diffuse parenchymal lung disease. Thorax. 2004;59(6):500-505.
55. Ryerson CJ, Vittinghoff E, Ley B, et al. Predicting survival across chronic interstitial lung disease: the ILD-GAP model. Chest. 2014;145(4):723-728.
77. Ryerson CJ, Urbania TH, Richeldi L, et al. Prevalence and prognosis of unclassifiable interstitial lung disease. Eur Respir J. 2013;42(3): 750-757.
56. Fischer A, Brown KK, Du Bois RM, et al. Mycophenolate mofetil improves lung function in connective tissue disease-associated interstitial lung disease. J Rheumatol. 2013;40(5):640-646.
78. Troy L, Glaspole I, Goh N, et al. Prevalence and prognosis of unclassifiable interstitial lung disease. Eur Respir J. 2014;43(5): 1529-1530.
57. Qureshi RA, Ahmed TA, Grayson AD, Soorae AS, Drakeley MJ, Page RD. Does lung biopsy help patients with interstitial lung disease? Eur J Cardiothorac Surg. 2002;21(4):621-626; discussion 626.
79. Cottin V, Wells A. Unclassified or unclassifiable interstitial lung disease: confusing or helpful disease category? Eur Respir J. 2013;42(3):576-579.
1140 Recent Advances in Chest Medicine
[
151#5 CHEST MAY 2017
]