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COUNTERPOINT: Should BAL Be Routinely Performed in the Diagnostic Evaluation of Idiopathic Pulmonary Fibrosis? No

2017; Elsevier BV; Volume: 152; Issue: 5 Linguagem: Inglês

10.1016/j.chest.2017.08.1172

1931-3543

Joshua J. Mooney, Harold R. Collard,

Eosinophilic Disorders and Syndromes

Idiopathic pulmonary fibrosis (IPF) is a progressive fibrotic interstitial lung disease (ILD) that is characterized morphologically by the presence of subpleural fibrosis and fibroplasia in what has been termed the usual interstitial pneumonia (UIP) pattern. Increasing evidence supports the concept of IPF as an age-related disease of alveolar epithelial cell dysfunction,1Wolters P.J. Collard H.R. Jones K.D. Pathogenesis of idiopathic pulmonary fibrosis.Ann Rev Pathol. 2014; 9: 157-179Crossref PubMed Scopus (510) Google Scholar and its management is distinct from other fibrotic ILDs that mimic it, in particular fibrotic hypersensitivity pneumonitis (HP).2Richeldi L. du Bois R.M. Raghu G. et al.Efficacy and safety of nintedanib in idiopathic pulmonary fibrosis.N Engl J Med. 2014; 370: 2071-2082Crossref PubMed Scopus (2745) Google Scholar, 3King Jr., T.E. Bradford W.Z. Castro-Bernardini S. et al.A phase 3 trial of pirfenidone in patients with idiopathic pulmonary fibrosis.N Engl J Med. 2014; 370: 2083-2092Crossref PubMed Scopus (2452) Google Scholar, 4Raghu G. Collard H.R. Egan J.J. 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: 788-824Crossref PubMed Scopus (5369) Google Scholar, 5Raghu G. Rochwerg B. Zhang Y. et al.An official ATS/ERS/JRS/ALAT clinical practice guideline: treatment of idiopathic pulmonary fibrosis. An update of the 2011 clinical practice guideline.Am J Respir Crit Care Med. 2015; 192: e3-e19Crossref PubMed Scopus (1312) Google Scholar The diagnosis of IPF involves two core challenges: identifying a UIP pattern and ruling out the UIP pattern’s known causes. Under current IPF diagnostic guidelines, there is consensus regarding the former: The presence of specific features on high-resolution CT (HRCT) scanning of the chest allow a UIP pattern to be noninvasively identified in selected patients, obviating the need for histopathologic diagnosis. The remaining patients require a surgical lung biopsy procedure.4Raghu G. Collard H.R. Egan J.J. 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: 788-824Crossref PubMed Scopus (5369) Google Scholar Guidance on ruling out known causes of a UIP pattern, however, is less forthcoming, and it is left to the pulmonologist to ferret out alternatives through largely subjective means. It is in this context that we consider the use of BAL and the evaluation of BAL fluid cellularity as a diagnostic tool. BAL provides a fluid-based sampling of a lung subsegment’s small airways and alveoli, and the diagnostic value of the percentage of macrophages, neutrophils, lymphocytes, and eosinophils in BAL fluid has been studied for many decades.6Stoller J.K. Rankin J.A. Reynolds H.Y. The impact of bronchoalveolar lavage cell analysis on clinicians’ diagnostic reasoning about interstitial lung disease.Chest. 1987; 92: 839-843Abstract Full Text Full Text PDF PubMed Google Scholar, 7Meyer K.C. Raghu G. Baughman R.P. 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: 1004-1014Crossref PubMed Scopus (687) Google Scholar Particular attention has been given to the diagnostic value of BAL lymphocytosis in distinguishing fibrotic HP from IPF.7Meyer K.C. Raghu G. Baughman R.P. 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: 1004-1014Crossref PubMed Scopus (687) Google Scholar, 8Ohshimo S. Bonella F. Cui A. et al.Significance of bronchoalveolar lavage for the diagnosis of idiopathic pulmonary fibrosis.Am J Respir Crit Care Med. 2009; 179: 1043-1047Crossref PubMed Scopus (190) Google Scholar In this counterpoint paper, we consider the position that BAL should not be routinely performed in the diagnostic evaluation of IPF by reviewing two sources: (1) academic societal guidelines that have considered this same question and (2) published data that inform the test characteristics of BAL lymphocytosis. In 2011, an international guideline committee sponsored by multiple academic societies established diagnostic criteria for IPF that require a multidisciplinary evaluation of clinical, radiological, and (when necessary) histopathologic features.4Raghu G. Collard H.R. Egan J.J. 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: 788-824Crossref PubMed Scopus (5369) Google Scholar As part of the committee’s commentary on the clinical evaluation, they considered the evidence behind the diagnostic utility of BAL. It is worth quoting from their discussion: “It is of particular importance to evaluate patients thoroughly for possible chronic HP, since such patients may mimic IPF.” “…BAL showing a lymphocytosis of 40% or greater may suggest occult HP in this setting, prompting further investigation for environmental exposures and possibly a surgical lung biopsy.” In summary, however, the committee wrote, “It is unclear whether BAL adds significant diagnostic specificity to a careful exposure history and clinical evaluation,” and their recommendation was that it should not be performed in the majority of patients based on the available data. In assessing the value of a diagnostic procedure such as BAL, its test characteristics—in particular its likelihood ratios, need to be considered. Likelihood ratios indicate by how much a diagnostic test result will change the pretest probability of a diagnosis.9Jaeschke R. Guyatt G.H. Sackett D.L. Users' guides to the medical literature. III. How to use an article about a diagnostic test. B. What are the results and will they help me in caring for my patients? The Evidence-Based Medicine Working Group.JAMA. 1994; 271: 703-707Crossref PubMed Scopus (2152) Google Scholar If the “posttest probability” (the probability of a diagnosis after the test result) is greater than the diagnostic threshold for clinical certainty, the test result is considered definitive, and a diagnosis is established. For conclusive results from diagnostic tests, large likelihood ratios are often required (Fig 1). Published data on the test characteristics of BAL in patients with fibrotic ILD are limited but suggest that BAL lymphocytosis is not specific to HP (Table 1).8Ohshimo S. Bonella F. Cui A. et al.Significance of bronchoalveolar lavage for the diagnosis of idiopathic pulmonary fibrosis.Am J Respir Crit Care Med. 2009; 179: 1043-1047Crossref PubMed Scopus (190) Google Scholar, 10Pardo A. Smith K.M. Abrams J. et al.CCL18/DC-CK-1/PARC up-regulation in hypersensitivity pneumonitis.Journal Leukoc Biol. 2001; 70: 610-616PubMed Google Scholar, 11Yoshizawa Y. Ohtani Y. Hayakawa H. Sato A. Suga M. Ando M. Chronic hypersensitivity pneumonitis in Japan: a nationwide epidemiologic survey.J Allergy Clin Immunol. 1999; 103: 315-320Abstract Full Text Full Text PDF PubMed Google Scholar, 12Lacasse Y. Selman M. Costabel U. et al.Clinical diagnosis of hypersensitivity pneumonitis.Am J Respir Crit Care Med. 2003; 168: 952-958Crossref PubMed Scopus (500) Google Scholar, 13Veeraraghavan S. Latsi P.I. Wells A.U. et al.BAL findings in idiopathic nonspecific interstitial pneumonia and usual interstitial pneumonia.Eur Respir J. 2003; 22: 239-244Crossref PubMed Scopus (134) Google Scholar Unfortunately, these publications have for the most part not distinguished between subacute and fibrotic HP, which makes extrapolation of their findings to the clinical scenario being discussed problematic.8Ohshimo S. Bonella F. Cui A. et al.Significance of bronchoalveolar lavage for the diagnosis of idiopathic pulmonary fibrosis.Am J Respir Crit Care Med. 2009; 179: 1043-1047Crossref PubMed Scopus (190) Google Scholar, 10Pardo A. Smith K.M. Abrams J. et al.CCL18/DC-CK-1/PARC up-regulation in hypersensitivity pneumonitis.Journal Leukoc Biol. 2001; 70: 610-616PubMed Google Scholar, 12Lacasse Y. Selman M. Costabel U. et al.Clinical diagnosis of hypersensitivity pneumonitis.Am J Respir Crit Care Med. 2003; 168: 952-958Crossref PubMed Scopus (500) Google Scholar Exploring the data from these publications is, nonetheless, instructive.Table 1Estimated Test Characteristics of BAL Lymphocytosis (> 40%) in Patients With ILDStudyStudy PopulationTest CharacteristicsaTest characteristics were rough “back of the envelope” estimates based on reported manuscript data and not derived from raw data.Pardo et al10Pardo A. Smith K.M. Abrams J. et al.CCL18/DC-CK-1/PARC up-regulation in hypersensitivity pneumonitis.Journal Leukoc Biol. 2001; 70: 610-616PubMed Google ScholarIPF, HPSensitivity, 90%; specificity, 78%; positive LR, 4; negative LR, 0.1 for HPLacasse et al12Lacasse Y. Selman M. Costabel U. et al.Clinical diagnosis of hypersensitivity pneumonitis.Am J Respir Crit Care Med. 2003; 168: 952-958Crossref PubMed Scopus (500) Google ScholarAll ILDSensitivity, 81%; specificity, 93%; positive LR, 12; negative LR, 0.2 for HPOhshimo et al8Ohshimo S. Bonella F. Cui A. et al.Significance of bronchoalveolar lavage for the diagnosis of idiopathic pulmonary fibrosis.Am J Respir Crit Care Med. 2009; 179: 1043-1047Crossref PubMed Scopus (190) Google ScholarIPF, HP, NSIPSensitivity, 100%; specificity, 97%; positive LR, 36; negative LR, 0 for HPHP = hypersensitivity pneumonitis; ILD = interstitial lung disease; IPF = idiopathic pulmonary fibrosis; LR = likelihood ratio; NSIP = nonspecific interstitial pneumonia.a Test characteristics were rough “back of the envelope” estimates based on reported manuscript data and not derived from raw data. Open table in a new tab HP = hypersensitivity pneumonitis; ILD = interstitial lung disease; IPF = idiopathic pulmonary fibrosis; LR = likelihood ratio; NSIP = nonspecific interstitial pneumonia. The first study by Pardo et al10Pardo A. Smith K.M. Abrams J. et al.CCL18/DC-CK-1/PARC up-regulation in hypersensitivity pneumonitis.Journal Leukoc Biol. 2001; 70: 610-616PubMed Google Scholar was small, reporting on 10 patients with subacute or chronic HP and nine patients with IPF. Our “back of the envelope” estimates performed for this counterpoint paper using the reported mean and SDs for lymphocyte counts in the two populations generates a positive likelihood ratio for BAL lymphocytosis (defined as ≥ 40%) of only 4. The negative likelihood ratio, however, is approximately 0.13. The second study by Lacasse et al12Lacasse Y. Selman M. Costabel U. et al.Clinical diagnosis of hypersensitivity pneumonitis.Am J Respir Crit Care Med. 2003; 168: 952-958Crossref PubMed Scopus (500) Google Scholar was much larger, with 199 patients with subacute or chronic HP and 462 with other ILDs (226 of whom had IPF). Our rough back of the envelope estimates generate a more powerful estimated positive likelihood ratio of 12 and a negative likelihood ratio of 0.2 for HP given a BAL lymphocytosis (again defined as ≥ 40%). When lowering the lymphocytosis threshold to 30%, the positive likelihood ratio for HP decreases to approximately 3. There are many caveats to these likelihood ratio estimates, perhaps most centrally that the presence of BAL lymphocytosis was considered part of the diagnostic criteria for HP (an example of incorporation bias). A third study by Ohshimo et al8Ohshimo S. Bonella F. Cui A. et al.Significance of bronchoalveolar lavage for the diagnosis of idiopathic pulmonary fibrosis.Am J Respir Crit Care Med. 2009; 179: 1043-1047Crossref PubMed Scopus (190) Google Scholar performed BAL in 74 patients with suspected IPF who did not undergo a biopsy procedure. Six of these patients demonstrated lymphocytosis (defined as > 30%) and were accordingly classified as having non-IPF. Three of these patients were considered to have nonspecific interstitial pneumonia (two cases were later proved by biopsy procedures), and three patients were considered clinically to have chronic HP based on “histories of exposure to relevant environmental antigens, positive serum precipitans, and a favorable clinical course after avoidance of antigens and the administration of corticosteroids.” Although these findings suggest a much higher positive likelihood ratio for BAL lymphocytosis, it is important to note that none of the 68 patients considered to have IPF underwent biopsy procedures, and the presence of just a few patients with HP among this group of 68 would reduce the likelihood estimates to the range suggested by Pardo et al10Pardo A. Smith K.M. Abrams J. et al.CCL18/DC-CK-1/PARC up-regulation in hypersensitivity pneumonitis.Journal Leukoc Biol. 2001; 70: 610-616PubMed Google Scholar and Lacasse et al.12Lacasse Y. Selman M. Costabel U. et al.Clinical diagnosis of hypersensitivity pneumonitis.Am J Respir Crit Care Med. 2003; 168: 952-958Crossref PubMed Scopus (500) Google Scholar What do we conclude from these data? First, we can appreciate why the IPF guideline committee recommended against the routine use of BAL in the diagnostic evaluation of IPF. The data simply are not robust enough to support it. Second, we desperately need studies of well-characterized cohorts with HRCT imaging, BAL analyses, and surgical lung biopsy specimens to address this question directly. Such studies would require the prospective assignment of a diagnosis (IPF, HP, or other) without knowledge of the BAL results, allowing for the subsequent examination of the test results of BAL in the absence of incorporation bias. Third, there is reason to believe that BAL may indeed be useful. Aside from the anecdotal experience its many proponents cite, the crude estimates of likelihood ratios from the literature suggest that the absence of BAL lymphocytosis in a patient with a reasonably high pretest probability of IPF (but not high enough to confirm the diagnosis) may push the posttest probability of IPF across the diagnostic threshold. Perhaps more critically, the presence of BAL lymphocytosis in a patient with clinically diagnosed (ie, HRCT imaging based) IPF may push the posttest probability of IPF back to less than the diagnostic threshold and suggest that a surgical lung biopsy procedure is needed. Role of sponsors: The sponsor had no role in the design of the study, the collection and analysis of the data, or the preparation of the manuscript. /cms/asset/938783e6-e56c-432e-8b5b-84936bd70996/mmc1.mp3Loading ... Download .mp3 (37.43 MB) Help with .mp3 files Audio POINT: Should BAL Be Routinely Performed in the Diagnostic Evaluation of Idiopathic Pulmonary Fibrosis? YesCHESTVol. 152Issue 5PreviewIn the era of evidence-based medicine, guideline recommendations should, whenever possible, be based on moderate- to high-quality evidence. However, this ideal is seldom attainable for diagnostic tests in interstitial lung disease (ILD). The value added by diagnostic surgical biopsy and multidisciplinary diagnosis (MDD) is accepted by most clinicians and underpins recommendations made in the 2011 American Thoracic Society/European Respiratory Society/Japanese Respiratory Society/Latin American Thoracic Association guideline for the diagnosis and management of idiopathic pulmonary fibrosis (IPF). Full-Text PDF Rebuttal From Drs Mooney and CollardCHESTVol. 152Issue 5PreviewThere is consensus agreement among all four authors of this Point and Counterpoint paper that the potential utility of BAL in the diagnostic evaluation of idiopathic pulmonary fibrosis (IPF) would result from its ability to exclude chronic hypersensitivity pneumonitis (HP) based on the BAL lymphocyte count.1,2 Our disagreement with Wells and Kokosi regarding the routine use of BAL is centered on whether there is sufficient data on the test characteristics of BAL lymphocytosis to justify a central role in clinical decision-making. Full-Text PDF Rebuttal From Drs Wells and KokosiCHESTVol. 152Issue 5PreviewThe South African philosopher Mokokoma Mokhonoana argued that “we usually learn from debates that we seldom learn from debates.” On this occasion, however, we can be forensic because we agree on certain essentials.1,2 We agree that the potential diagnostic utility of BAL in suspected idiopathic pulmonary fibrosis (IPF) lies in the detection of a BAL lymphocytosis, suggesting an alternative diagnosis, usually chronic hypersensitivity pneumonitis. We agree that the evidence base is inconclusive. This allows us to focus on two issues: the nature of “evidence” and the goals of BAL evaluation. Full-Text PDF