raghu-et-al-2022-idiopathic-pulmonary-fibrosis-(an-update)-and-progressive-pulmonary-fibrosis-in-adults-an-official-ats.pdf

AMERICAN THORACIC SOCIETY DOCUMENTS Idiopathic Pulmonary Fibrosis (an Update) and Progressive Pulmonary Fibrosis in Adults An Official ATS/ERS/JRS/ALAT Clinical Practice Guideline Ganesh Raghu, Martine Remy-Jardin, Luca Richeldi, Carey C. Thomson, Yoshikazu Inoue, Takeshi Johkoh, Michael Kreuter, Da...

AMERICAN THORACIC SOCIETY DOCUMENTS Idiopathic Pulmonary Fibrosis (an Update) and Progressive Pulmonary Fibrosis in Adults An Official ATS/ERS/JRS/ALAT Clinical Practice Guideline Ganesh Raghu, Martine Remy-Jardin, Luca Richeldi, Carey C. Thomson, Yoshikazu Inoue, Takeshi Johkoh, Michael Kreuter, David A. Lynch, Toby M. Maher, Fernando J. Martinez, Maria Molina-Molina, Jeffrey L. Myers, Andrew G. Nicholson, Christopher J. Ryerson, Mary E. Strek, Lauren K. Troy, Marlies Wijsenbeek, Manoj J. Mammen, Tanzib Hossain, Brittany D. Bissell, Derrick D. Herman, Stephanie M. Hon, Fayez Kheir, Yet H. Khor, Madalina Macrea, Katerina M. Antoniou, Demosthenes Bouros, Ivette Buendia-Roldan, Fabian Caro, Bruno
s Selman, Crestani, Lawrence Ho, Julie Morisset, Amy L. Olson, Anna Podolanczuk, Venerino Poletti, Moise Thomas Ewing, Stephen Jones, Shandra L. Knight, Marya Ghazipura, and Kevin C. Wilson; on behalf of the
n American Thoracic Society, European Respiratory Society, Japanese Respiratory Society, and Asociacio
rax Latinoamericana de To THIS OFFICIAL CLINICAL PRACTICE GUIDELINE WAS APPROVED BY
LATINOAMERICANA DE To
RAX FEBRUARY 2022 ASOCIACION THE AMERICAN THORACIC SOCIETY, EUROPEAN RESPIRATORY SOCIETY, JAPANESE RESPIRATORY SOCIETY, Abstract AND with evidence-based recommendations using the GRADE approach. Background: This American Thoracic Society, European Respiratory Society, Japanese Respiratory Society, and Asociaci
on Latinoamericana de T
orax guideline updates prior idiopathic pulmonary fibrosis (IPF) guidelines and addresses the progression of pulmonary fibrosis in patients with interstitial lung diseases (ILDs) other than IPF. Methods: A committee was composed of multidisciplinary experts in ILD, methodologists, and patient representatives. 1) Update of IPF: Radiological and histopathological criteria for IPF were updated by consensus. Questions about transbronchial lung cryobiopsy, genomic classifier testing, antacid medication, and antireflux surgery were informed by systematic reviews and answered with evidence-based recommendations using the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) approach. 2) Progressive pulmonary fibrosis (PPF): PPF was defined, and then radiological and physiological criteria for PPF were determined by consensus. Questions about pirfenidone and nintedanib were informed by systematic reviews and answered Results: 1) Update of IPF: A conditional recommendation was made to regard transbronchial lung cryobiopsy as an acceptable alternative to surgical lung biopsy in centers with appropriate expertise. No recommendation was made for or against genomic classifier testing. Conditional recommendations were made against antacid medication and antireflux surgery for the treatment of IPF. 2) PPF: PPF was defined as at least two of three criteria (worsening symptoms, radiological progression, and physiological progression) occurring within the past year with no alternative explanation in a patient with an ILD other than IPF. A conditional recommendation was made for nintedanib, and additional research into pirfenidone was recommended. Conclusions: The conditional recommendations in this guideline are intended to provide the basis for rational, informed decisions by clinicians. Keywords: idiopathic pulmonary fibrosis; progressive pulmonary fibrosis; radiology; histopathology You may print one copy of this document at no charge. However, if you require more than one copy, you must place a reprint order. Domestic reprint orders: [email protected]; international reprint orders: [email protected]. Am J Respir Crit Care Med Vol 205, Iss 9, pp e18–e47, May 1, 2022 Copyright © 2022 by the American Thoracic Society DOI: 10.1164/rccm.202202-0399ST Internet address: www:atsjournals:org e18 American Journal of Respiratory and Critical Care Medicine Volume 205 Number 9 | May 1 2022 AMERICAN THORACIC SOCIETY DOCUMENTS Contents Introduction Methods Part I: Update on Diagnosis and Treatment of IPF Radiological Features of UIP Histopathological Features of UIP Evidence-based Recommendations for Diagnosis of IPF Diagnostic Approach Introduction Idiopathic pulmonary fibrosis (IPF) is a chronic, fibrosing interstitial pneumonia of unknown cause that is associated with radiological and histologic features of usual interstitial pneumonia (UIP). It occurs primarily in older adults, is characterized by progressive worsening of dyspnea and lung function, and has a poor prognosis. Diagnosis and management of IPF were addressed in prior guidelines (1–3). A formal American Thoracic Society (ATS) and European Respiratory Society (ERS) proposal process determined that several topics from the previous guidelines warrant reassessment, including the following: radiological and histopathological features of UIP, diagnostic criteria, diagnostic and treatment approaches, and prior evidencebased recommendations about antacid medications and transbronchial lung cryobiopsy (TBLC). In addition, it was decided that new questions about antireflux surgery and genomic classifier testing should be addressed. The acceptance of antifibrotic therapies for IPF led to the investigation of such Evidence-based Recommendations for Treatment of IPF Management Approach Future Directions Part II: Diagnosis and Treatment of PPF in Fibrotic ILD, Other than IPF Definition of PPF Physiological Criteria for PPF Radiological Criteria for PPF therapies in other fibrotic lung diseases. While the IPF guidelines were being updated, a clinical trial reporting a beneficial effect of antifibrotic medication in interstitial lung diseases (ILDs) other than IPF that manifest progressive pulmonary fibrosis (PPF) was published (4, 5), prompting a paradigm shift toward an en bloc approach to antifibrotic therapy. Given the importance and timeliness of the issue, the guideline committee was approved to expand its scope to also define progression of pulmonary fibrosis and to decide whether the en bloc approach to antifibrotic therapy should continue, or whether therapy should be restricted to specific types of progressive ILD. These guidelines for the diagnosis and treatment of IPF and other types of PPF are the result of a collaboration among the ATS, ERS, Japanese Respiratory Society (JRS), and Asociaci
on Latinoamericana de T
orax (ALAT). They are intended to provide the basis for rational, informed decisions. The recommendations should never be considered absolute requirements by anyone who evaluates the actions of a healthcare professional. Evidence-based Recommendations for Treatment of PPF, Other than IPF Future Directions Conclusions Methods Methods including conflict-of-interest management were established a priori and are described in the online supplement. The document can be conceptualized in two parts. Narrative portions (e.g., radiological criteria, histopathological criteria, physiological criteria, definitions) were created using consensus by discussion. Guideline portions address specific questions related to TBLC, genomic classifier testing, antacid medication, antireflux surgery for IPF, and pirfenidone and nintedanib for PPF. These sections are compliant with the Institute of Medicine standards for trustworthy guidelines (6) and yield recommendations that were informed by systematic reviews and were formulated and graded using the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) approach (7) (Table 1). Evidence-based recommendations were formulated by discussion followed by voting. Briefly, committee members were provided the following options: a strong recommendation for a course of action, a ORCID IDs: 0000-0001-7506-6643 (G.R.); 0000-0003-1944-4288 (M.R.-J.); 0000-0001-8594-1448 (L.R.); 0000-0002-5861-0683 (C.C.T.); 0000-0003-3994-874X (Y.I.); 0000-0003-1237-2349 (T.J.); 0000-0003-4402-2159 (M.K.); 0000-0002-6329-2325 (D.A.L.); 0000-0001-7192-9149 (T.M.M.); 0000-0002-2412-3182 (F.J.M.); 0000-0002-1852-1723 (M.M.-M.); 0000-0001-8247-3028 (J.L.M.); 0000-0002-7671-1023 (M.E.S.); 0000-0002-7426-336X (L.K.T.); 0000-0002-4527-6962 (M.W.); 0000-0003-0343-3234 (M.J.M.); 0000-0002-1995-7828 (T.H.); 0000-0002-7345-9731 (B.D.B.); 0000-0002-0390-8407 (S.M.H.); 0000-0002-5434-9342 (Y.H.K.); 0000-0002-5352-9587 (M.M.); 0000-0002-2825-506X (I.B.-R.); 0000-0003-2484-1923 (F.C.); 0000-0002-2961-3455 (B.C.); 0000-0002-5368-0412 (A.L.O.); 0000-0002-9559-1485 (A.P.); 0000-0002-1022-4783 (M.S.); 0000-0002-4404-3833 (S.L.K.); 0000-0003-4328-6822 (M.G.); 0000-0003-4429-2263 (K.C.W.).
n Latinoamericana de Supported by the American Thoracic Society, European Respiratory Society, Japanese Respiratory Society, and Asociacio
rax. To An Executive Summary of this document is available at http://www.atsjournals.org/doi/suppl/10.1164/rccm.202202-0399ST. Correspondence and requests for reprints should be addressed to Ganesh Raghu, M.D., 1959 NE Pacific Avenue, University of Washington Medical Center-Montlake Campus, Center for Interstitial Lung Diseases, Medical Specialty Clinics (3rd floor), Box 356175, Seattle, WA 98195. E-mail: [email protected]. This article has an online supplement, which is accessible from this issue’s table of contents at www.atsjournals.org. American Thoracic Society Documents e19 AMERICAN THORACIC SOCIETY DOCUMENTS conditional recommendation for a course of action, a conditional recommendation against a course of action, a strong recommendation against a course of action, and abstention (Table 2). Abstention was appropriate whenever a committee member was unwilling to commit for or against the proposed course of action, such as when there was insufficient evidence, or the committee member had insufficient expertise or a self-realized bias. Three outcomes were possible: 1. 2. 3. Greater than 20% abstentions indicated that there was an insufficient quorum for decision making. If the primary reason for the abstentions was insufficient evidence, a research recommendation was also made. Fewer than 20% abstentions with .70% agreement on the appropriate course of action yielded a graded recommendation. This result was indicated by a statement beginning “We recommend … ” for strong recommendations or “We suggest … ” for conditional recommendations. Fewer than 20% abstentions with ,70% agreement on the appropriate course of action yielded no recommendation because of insufficient agreement among the committee members regarding the appropriate course of action. This result was indicated by the statement, “We make no recommendation for or against … because of insufficient agreement among the committee members.” Part I: Update on Diagnosis and Treatment of IPF Radiological Features of UIP Radiological features of UIP, the hallmark of IPF, were described in detail in the 2018 guidelines for diagnosis of IPF (2). The guideline committee concluded that several radiological features warrant reiteration in the current guideline for emphasis, and they reconsidered the categories of high-resolution computed tomography (HRCT) patterns. Spectrum of HRCT findings in IPF. Lung fibrosis is confidently recognized when traction bronchiectasis/bronchiolectasis (Figure 1) and/or honeycombing (Figure 2) are identified, although honeycombing must be distinguished from paraseptal emphysema (Figure 3) and airspace enlargement with fibrosis (Figure 4). Pathologic–computed tomography correlations have demonstrated that honeycombing and traction bronchiolectasis are closely related. Honeycombing corresponds to bronchiolar cysts, developed after collapse of fibrotic alveolar septa and dilatation of terminal airways (8, 9). The cystic structures sometimes can be followed throughout the lobular core and seem to be connected with each other and are in continuity with the bronchial tree (10). Honeycombing cysts consist of both dilatation of peripheral airspaces due to surrounding alveolar septal fibrosis and tangentially viewed traction bronchiolectasis (11). HRCT findings typical of UIP and honeycombing on HRCT correlate best with bronchiolectasis Table 1. Summary of Methods Methods Used Conflict-of-interest disclosure, vetting, and management prespecified Guideline committee multidisciplinary Guideline committee has patient representation Literature search strategy prespecified Multiple databases searched for relevant studies Titles and abstracts screened in duplicate Study selection criteria prespecified Study selection and data extraction performed in duplicate Studies aggregated by meta-analysis when possible GRADE approach used to formulate recommendations GRADE approach used to rate the strength of recommendation and quality of evidence Public commentary period Process exists to periodically reassess for updating Y Y Y Y Y Y Y Y Y Y Y N Y Definition of abbreviations: GRADE = Grading of Recommendations, Assessment, Development and Evaluation; N = no; Y = yes. e20 histologically (12). Recent observations have underlined that in IPF, the remodeling process appears to be a continuum from traction bronchiectasis to honeycombing and that conceptual separation of the two processes may be misleading (13). Identification of traction bronchiectasis/ bronchiolectasis and honeycombing on computed tomography (CT) scans is associated with moderate interobserver agreement (14–16). The UIP pattern is a hallmark of IPF (IPF-UIP), but it can also be seen in patients with fibrotic hypersensitivity pneumonitis (HP) (Figure 5), connective tissue disease (CTD) (CTD-UIP) (Figure 6), or exposurerelated ILDs. HP-UIP and CTD-UIP may sometimes be suspected on the basis of imaging appearance but are often indistinguishable radiologically from IPF-UIP. Pleuroparenchymal fibroelastosis may be seen in 6–10% of cases of IPF (17, 18) (Figure 7); it may be associated with more rapid decline in lung function, higher risk of pneumothorax and pneumomediastinum, and poorer survival (17). Probable UIP pattern in the diagnostic approach to IPF. Four HRCT categories were defined in the 2018 guidelines for diagnosis of IPF: UIP pattern, probable UIP pattern, indeterminate for UIP pattern, and alternative diagnosis (2) (Figures 1, 2, 4, and 8). Merger of the UIP and probable UIP patterns into a single category was considered; however, the guideline committee decided to retain the four categories with minor modifications for the purpose of clarity (Table 3). There were several reasons that merging the UIP and probable UIP categories was considered: 1) there is increasing evidence that patients with the probable UIP pattern and UIP pattern on HRCT have similar disease behavior and clinical courses (19–21); 2) the likelihood of histologic confirmation of UIP in patients with the probable UIP pattern ranges from 80% to 85% (19, 22, 23); and 3) in the appropriate clinical context, histopathological confirmation of the UIP pattern is not required to ascertain the diagnosis of IPF in patients with either the probable UIP pattern or the UIP pattern (2, 24, 25). Despite these reasons, the guideline committee opted to maintain the differentiation between the two patterns for several reasons: 1) studies describing the correlation of probable UIP with American Journal of Respiratory and Critical Care Medicine Volume 205 Number 9 | May 1 2022 AMERICAN THORACIC SOCIETY DOCUMENTS Table 2. Implications of the Guideline Recommendations Strong Recommendation (“We Recommend … ”) Conditional Recommendation (“We Suggest … ”) For patients The overwhelming majority of individuals in this situation would want the recommended course of action, and only a small minority would not. The majority of individuals in this situation would want the suggested course of action, but a sizable minority would not. For clinicians The overwhelming majority of individuals should receive the recommended course of action. Adherence to this recommendation according to the guideline could be used as a quality criterion or performance indicator. Formal decision aids are not likely to be needed to help individuals make decisions consistent with their values and preferences. Different choices will be appropriate for different patients, and you must help each patient arrive at a management decision consistent with her or his values and preferences. Decision aids may be useful to help individuals make decisions consistent with their values and preferences. Clinicians should expect to spend more time with patients when working toward a decision. For policy makers The recommendation can be adapted as policy in most situations, including for the use as performance indicators. Policy making will require substantial debates and involvement of many stakeholders. Policies are also more likely to vary among regions. Performance indicators would have to focus on the fact that adequate deliberation about the management options has taken place. It is the right course of action for .95% of patients. It is the right course of action for .50% of patients. “Just do it.” “Slow down, think about it, discuss it with the patient.” You would be willing to tell a colleague who did not follow the recommendation that he/she did the wrong thing. You would not be willing to tell a colleague who did not follow the recommendation that he/she did the wrong thing; it is “style” or “equipoise.” The recommended course of action may be an appropriate performance measure. The recommended course of action is not appropriate for a performance measure. From the GRADE working group Additional conceptualization from the ATS/ ERS/JRS/ALAT Idiopathic Pulmonary Fibrosis (an Update) and Progressive Pulmonary Fibrosis Guidelines panel discussion
n Latinoamericana de To
rax; ATS = American Thoracic Society; ERS = European Respiratory Society; Definition of abbreviations: ALAT = Asociacio GRADE = Grading of Recommendations, Assessment, Development and Evaluation; JRS = Japanese Respiratory Society. Adapted from Reference 7. histopathological UIP are from expert settings, and correlation in alternative settings is unknown; 2) there is evidence suggesting that patients with probable UIP might have better survival (19, 26); 3) the predictive value of the probable UIP CT pattern for histologic UIP is slightly lower than for the UIP CT pattern, suggesting that the probable UIP CT pattern may show more overlap with other fibrotic lung diseases such as fibrotic HP; and 4) there is evidence that the predictive value of a probable UIP pattern for histologic UIP is lower in individuals with relatively mild American Thoracic Society Documents fibrosis and in younger individuals (27). Although the UIP pattern and probable UIP pattern remain separate (Figure 9), the diagnostic approaches for these entities are similar (Figure 10), and histologic confirmation is usually unnecessary unless there is clinical concern for an alternative diagnosis (25). Histopathological Features of UIP The histopathological criteria that characterize UIP and probable UIP were reviewed and confirmed. A diagnosis of UIP made by biopsy is predicated on a combination of the following: 1) patchy dense fibrosis with architectural distortion (i.e., destructive scarring and/or honeycombing); 2) a predilection for subpleural and paraseptal lung parenchyma; 3) fibroblast foci; and 4) the absence of features that suggest an alternative diagnosis (2). When all of these features are present, a UIP pattern can be established with confidence. “Probable UIP” refers to biopsies in which some of these findings are present in the absence of features to suggest an alternative diagnosis. e21 AMERICAN THORACIC SOCIETY DOCUMENTS Figure 1. Traction bronchiectasis/bronchiolectasis. Axial, sagittal, and coronal computed tomography images show subpleural-predominant, lower lung–predominant reticular abnormality with traction bronchiectasis (arrows). Traction bronchiectasis/bronchiolectasis represents irregular bronchial and/or bronchiolar dilatation caused by surrounding retractile fibrosis; distorted airways are thus identified in a background of reticulation and/or ground-glass attenuation. On contiguous high-resolution computed tomography sections, the dilated bronchi or bronchioles can be tracked back toward more central bronchi. The pattern in this patient represents the probable usual interstitial pneumonia pattern. The committee concluded that the evolving use of TBLC merits commentary. Application of the histopathological criteria for UIP is more challenging with TBLC specimens because 1) the subpleural predominance of pathologic changes may not be readily appreciated and 2) the potential for sampling error results in less confident exclusion of features that may suggest an alternative diagnosis. Compared with surgical lung biopsy (SLB), TBLC is more likely to demonstrate a probable UIP pattern than a definite UIP pattern given the limited sampling of subpleural lung parenchyma in most cases (28). Nevertheless, e22 a combination of patchy fibrosis, fibroblast foci, and the absence of features to suggest an alternative diagnosis is usually sufficient to establish a probable UIP pattern on TBLC (29). Combining UIP and probable UIP patterns in the context of multidisciplinary discussion (MDD) results in comparable rates of diagnostic agreement for SLB and TBLC in patients with IPF (28). Evidence-based Recommendations for Diagnosis of IPF We suggest that TBLC be regarded as an acceptable alternative to SLB for making a histopathological diagnosis in patients with ILD of undetermined type in medical centers with experience performing and interpreting TBLC (conditional recommendation, very low quality evidence). Background. The 2018 guidelines for diagnosis of IPF addressed TBLC in patients with ILD of undetermined type but failed to garner enough agreement to make a consensus recommendation for or against TBLC (2). Additional studies have been published since the previous guideline; therefore, the guideline committee decided to reconsider the evidence pertaining to TBLC. In contrast, the 2018 diagnosis of IPF American Journal of Respiratory and Critical Care Medicine Volume 205 Number 9 | May 1 2022 AMERICAN THORACIC SOCIETY DOCUMENTS Figure 2. Honeycombing. Axial, sagittal, and coronal computed tomography images show subpleural-predominant, lower lung–predominant reticular abnormality with honeycombing (arrowheads). Honeycombing is defined by clustered, thick-walled, cystic spaces of similar diameters, measuring between 3 and 10 mm but up to 2.5 cm in size. The size and number of cysts often increase as the disease progresses. Often described in the literature as being layered, a single layer of subpleural cysts is also a manifestation of honeycombing. Honeycombing is an essential computed tomography criterion for typical (“definite”) usual interstitial pneumonia–idiopathic pulmonary fibrosis pattern when seen with a basal and peripheral predominance. In this pattern, honeycombing is usually associated with traction bronchiolectasis and a varying degree of ground-glass attenuation. guidelines’ recommendation pertaining to SLB was not reevaluated (2). The committee concluded that there is insufficient new evidence to warrant reconsideration of the SLB recommendation at this time; in addition, a separate ERS task force may soon be addressing the topic. Summary of evidence. The committee asked, “Should patients with newly detected ILD of undetermined type who are clinically suspected of having IPF undergo TBLC to obtain samples to make a histopathological diagnosis?” The systematic review that American Thoracic Society Documents informed the committee’s recommendation is being published independently (30); we summarize the salient findings. Diagnostic yield was designated as a critical outcome. The remaining outcomes were rated as important outcomes, including diagnostic agreement and various complications. The systematic review identified 40 studies that evaluated TBLC in patients with ILD of undetermined type (28, 31–69). The studies ranged in size from 12 to 699 patients and used either a 1.9- or 2.4-mm cryoprobe with fluoroscopic guidance. Five of the studies were prospective (28, 32, 48, 60, 69), most used deep sedation, most used rigid bronchoscopy, and the number and location of samples varied widely across studies. Regarding selection of diagnostic yield rather than sensitivity and specificity as the critical outcome, diagnostic yield is appropriate if the intervention is the reference standard, but sensitivity and specificity are appropriate if the intervention is compared with a reference standard. In this case, histopathological diagnosis was chosen a priori as the reference standard, e23 AMERICAN THORACIC SOCIETY DOCUMENTS Figure 3. Paraseptal emphysema. Axial and coronal computed tomography images show relatively large subpleural cysts of paraseptal emphysema (arrows), mainly in the upper lobes. Centrilobular emphysema is also present. The subpleural cysts of paraseptal emphysema usually occur in a single layer and are larger than honeycomb cysts (typically .1 cm); they are not associated with other features of fibrosis such as reticular abnormality or traction bronchiectasis. making diagnostic yield the appropriate outcome. Clinical, radiological, and histopathological criteria applied by MDD were not chosen as the reference standard, because this would likely lead to misleading overestimates of sensitivity and specificity because of “incorporation bias.” Incorporation bias occurs when the test results are a component of the reference standard; in this case, histopathology obtained by TBLC is a key component of the diagnostic criteria considered during MDD. DIAGNOSTIC YIELD. Diagnostic yield was defined as the number of procedures e24 that yielded a histopathological diagnosis divided by the total number of procedures performed. The diagnostic yield of TBLC in patients with ILD of undetermined type was 79% (28, 31–38, 40, 41, 44–47, 50–52, 54, 55, 57, 58, 60–63, 65, 66, 68). There was no difference in diagnostic yield across subgroups related to publication date, study size, or cryoprobe size. Only sample number appeared to affect diagnostic yield, with a diagnostic yield of 85% when three or more samples were collected (28, 33, 38, 44, 45, 51, 55, 63, 66, 69) and a diagnostic yield of 77% or less when fewer samples were collected. DIAGNOSTIC AGREEMENT. Two studies reported agreement between the diagnostic interpretation of TBLC samples and SLB samples (28, 60). The larger study demonstrated 70.8% agreement, which increased to 76.9% diagnostic agreement after MDD (28). Post hoc analysis suggested that agreement of TBLC with SLB improves by taking more samples (29). In contrast, the smaller study reported diagnostic agreement of only 38% (60). COMPLICATIONS. Complications of TBLC included pneumothorax in 9% (28, 31, 33–35, 37, 39–43, 46, 48–50, 53–55, 60, 63, 68, 69) and any bleeding in 30% (28, 31, 33, 36, 39, 47, 50, 51, 55, 67–69). Severe bleeding, procedural mortality, exacerbations, respiratory infections, and persistent air leak were rare. QUALITY OF EVIDENCE. The quality of evidence was very low for all outcomes, meaning that the committee should have very low confidence in the estimated effects, and therefore, the effects should be interpreted with caution. The main reason for the very low quality rating was that most of the studies were uncontrolled case series, and many were limited by not enrolling consecutive patients (potential selection bias). Guideline committee conclusions. The original question and systematic review involved the comparison of TBLC versus no TBLC (i.e., TBLC followed by SLB, if needed, vs. going directly to SLB). However, the committee concluded that the comparison had become outdated because observations published during guideline development suggest that patients who have nondiagnostic findings on TBLC are likely to also have nondiagnostic findings on SLB. This changed the clinically meaningful comparison to TBLC versus SLB. Therefore, the committee compared the estimated 80% diagnostic yield of TBLC (according to the present systematic review) to the estimated 90% diagnostic yield of SLB (according to a previously published systematic review) (2) and also considered that the sampling techniques provide similar diagnostic confidence in the context of MDD (2). They also compared the 9% and rare risk of pneumothorax and severe bleeding, respectively, on TBLC with the 6% and rare risk of pneumothorax and severe bleeding, respectively, on SLB (2). The committee judged the comparison favorably when one considers that TBLC is less invasive and less costly than SLB. As a result, the committee concluded that TBLC may be considered an American Journal of Respiratory and Critical Care Medicine Volume 205 Number 9 | May 1 2022 AMERICAN THORACIC SOCIETY DOCUMENTS Figure 4. Airspace enlargement with fibrosis (AEF), also called smoking-related interstitial fibrosis, in a cigarette smoker. Axial and sagittal images show clustered asymmetric cysts that are larger and more irregular than typical honeycomb cysts, without traction bronchiectasis or other signs of fibrosis (arrows). Emphysema is also present. AEF is not regarded as a distinct form of idiopathic interstitial pneumonia but results from the presence of a greater amount of fibrosis than usually described in the classic definition of emphysema. acceptable alternative to SLB in experienced centers that have standardized their protocols to include steps to minimize risk and maximize diagnostic yield, as described in detail elsewhere (70). The committee emphasized the importance of the experience of the person performing the TBLC, the facilities, and the person interpreting the samples in the success of TBLC (as in SLB) and concluded that a conditional recommendation is more appropriate than a strong recommendation American Thoracic Society Documents to account for variation in capabilities across institutions. The committee also emphasized that TBLC may not be appropriate for all patients. Similar physiological criteria should be considered whether assessing a patient’s suitability for TBLC or SLB. Severe lung function derangement (e.g., FVC , 50% predicted, DLCO , 35%), moderate or severe pulmonary hypertension (estimated systolic pulmonary arterial pressure . 40 mm Hg), uncorrectable bleeding risk, and/or significant hypoxemia (PaO2 , 55–60 mm Hg) are associated with a higher risk of adverse outcomes and are considered relative contraindications (32, 71, 72). There are emerging data regarding the safety and diagnostic yield of TBLC in subjects in whom SLB would not be performed because of significant lung function impairment or comorbidities. Although there are inconsistencies across studies, the data suggest that TBLC may be a reasonable option in some patients at higher risk for major complications, particularly when performed in higher volume centers. One study of 96 subjects from two centers reported no difference in the rates of adverse outcomes or length of hospitalization in higher risk patients (body mass index . 35 kg/m2, age . 75 yr, FVC , 50%, DLCO , 30%, systolic pulmonary arterial pressure . 40 mm Hg, or significant cardiac disease) compared with lower risk patients (73). Another study of 699 patients undergoing TBLC reported that both pathological and final multidisciplinary diagnostic yield were lower in patients with significant lung function impairment (FVC , 50% and/or DLCO , 35%). However, there were no significant differences in complications (59). Finally, another study showed that modified Medical Research Council score > 2, FVC < 50%, and Charlson Comorbidity Index > 2 were factors that predicted early and overall hospital readmission in the following 90 days. The overall mortality in this study at 90 days was 0.78% (32). Guideline committee vote. The committee’s vote was as follows: strong recommendation to consider TBLC an appropriate alternative, 8 of 33 (24%); conditional recommendation to consider TBLC an appropriate alternative, 23 of 33 (70%); conditional recommendation to not consider TBLC an appropriate alternative, 2 of 33 (6%); and strong recommendation to not consider TBLC an appropriate alternative, 0 of 33 (0%). One participant abstained from voting because of insufficient expertise. Research needs. The evidence was notable for inconsistency across studies, with some groups reporting significantly higher diagnostic yields than others. This suggests the continued need for procedural standardization, with subsequent measurement of outcomes, adjustments, and reevaluation. e25 AMERICAN THORACIC SOCIETY DOCUMENTS Figure 5. Spectrum of computed tomography (CT) appearances in usual interstitial pneumonia (UIP) pattern due to hypersensitivity pneumonitis (HP). (A) Coronal CT section obtained at deep inspiration showing honeycombing with traction bronchiolectasis in the peripheral part of the right lower lobe (short arrows) and numerous hyperlucent lobules in the left lower lobe (long arrows). (B) Lobular air trapping was confirmed on expiratory CT. HP-UIP should be considered when fibrosis and honeycomb cysts predominate in the upper or mid lungs, when mosaic attenuation or three-density sign is present, or when the fibrosis appears diffuse in the axial plane. Figure 6. Usual interstitial pneumonia (UIP) pattern due to connective tissue disease (CTD-UIP) in a patient with dermatomyositis/scleroderma overlap. Axial and coronal images show sharply demarcated fibrosis with exuberant honeycombing in the lower lobes and in the anterior upper lobes. CTD-UIP should be considered when honeycomb cysts are extensive, occupying .70% of the fibrotic portions of the lung (exuberant honeycombing sign); when fibrotic abnormality is sharply demarcated on coronal images from the relatively normal upper lungs (straight-edge sign); and when there is relative increase in fibrosis in the anterior upper lobes (anterior upper lobe sign). e26 American Journal of Respiratory and Critical Care Medicine Volume 205 Number 9 | May 1 2022 AMERICAN THORACIC SOCIETY DOCUMENTS Figure 7. Combined pleuroparenchymal fibroelastosis and usual interstitial pneumonia patterns. Coronal computed tomography image shows dense subpleural fibrosis at the lung apices with traction bronchiectasis and upper lobe volume loss. There is subpleural reticular abnormality and honeycombing in both lower lobes. We make no recommendation for or against the addition of genomic classifier testing for the purpose of diagnosing UIP in patients with ILD of undetermined type who are undergoing transbronchial forceps biopsy, because of insufficient agreement among the committee members. Background. A genomic classifier was developed with machine learning and whole transcriptome RNA sequencing using lung tissue obtained by SLB. More recently, it was introduced and validated for lung tissue obtained by transbronchial forceps biopsy (74, 75). The appropriateness of genomic classifier testing in patients with ILD of unknown type has never been considered in the context of a clinical practice guideline. Summary of evidence. The committee asked, “Should genomic classifier testing be performed for the purpose of diagnosing UIP in patients with ILD of undetermined type who are undergoing transbronchial forceps biopsy?” The systematic review that informed the committee’s recommendation is published independently (76); we summarize the salient findings. Diagnostic test characteristics were rated as critical outcomes, while diagnostic agreement, diagnostic confidence, and the adverse consequences of misclassification were rated as important outcomes. American Thoracic Society Documents The systematic review identified four relevant studies, which included a total of 195 patients with ILD of unknown type (75, 77–79). All of the studies were accuracy studies. Two of the studies also measured agreement in the categorization of UIP and non-UIP when a genomic classifier was or was not used, as well as diagnostic confidence before and after the use of a genomic classifier (75, 77). DIAGNOSTIC TEST CHARACTERISTICS. All four studies reported diagnostic test characteristics of genomic classifier testing and were included in a meta-analysis (75, 77–79). The individual studies reported sensitivity ranging from 59% to 80% and specificity ranging from 78% to 100% using histopathological diagnosis from samples obtained by SLB, TBLC, or MDD as the reference standard. When aggregated by meta-analysis, genomic classifier testing identified the UIP pattern with sensitivity and specificity of 68% and 92%, respectively, in patients with ILD of unknown type. DIAGNOSTIC AGREEMENT AND Two studies reported diagnostic agreement and confidence (75, 77). Multidisciplinary teams evaluated anonymized clinical information, radiology results, and either molecular classifier or histopathology results to categorize patients as having UIP pattern or non-UIP pattern. CONFIDENCE. The studies then measured agreement of the categorizations obtained with and without genomic classifier testing, as well as diagnostic confidence before and after the use of genomic classifier data. One study reported agreement of 86% between categorical IPF or non-IPF diagnoses made using molecular classifier results or histopathology, with an increase in diagnostic confidence after the incorporation of genomic classifier data (75). The other study reported agreement of 88% between categorical IPF or non-IPF clinical diagnoses made by MDD with and without genomic classifier results, with an increase in the diagnostic confidence when genomic classifier results were considered (77). QUALITY OF EVIDENCE. The quality of evidence is determined by the critical outcomes, which was rated as low. There were well-done accuracy studies downgraded because of imprecision (wide confidence intervals and few patients), the maker of the diagnostic test funded three of the studies, and several of the individuals who developed the diagnostic test also conducted the studies (i.e., confirmation bias). Guideline committee conclusions. The guideline committee made no recommendation for or against genomic classifier testing, because of insufficient agreement among the committee members. There were two schools of thought among the committee members. Those who favored genomic classifier testing believed that the high specificity provided important diagnostic information that can be used in MDD and, therefore, may reduce the need for additional sampling for histopathology diagnosis. Those who argued against genomic classifier testing believed that a recommendation in favor of testing was premature because 1) the sensitivity needs to improve (otherwise, a negative result fails to definitively exclude UIP); 2) the downstream consequences of false-negative results need to be better understood; 3) additional studies are necessary to obtain more precise estimates of sensitivity and specificity; 4) existing data incompletely address the incremental diagnostic value conferred by genomic classifier testing beyond what clinical and radiological data already provide, particularly given the possibility of a UIP pattern’s existing in a variety of ILDs; 5) the results do not provide the granular details that histopathology provides and are useful only in the context of MDD; 6) the importance of identifying UIP is less clear in e27 AMERICAN THORACIC SOCIETY DOCUMENTS A B C Figure 8. Three of the four high-resolution computed tomography patterns of usual interstitial pneumonia (UIP): (A) UIP pattern (associated with some paraseptal and centrilobular emphysema in the upper lobes), (B) probable UIP pattern with fibrotic features in the lung periphery (and some centrilobular emphysema in the upper lobes), and (C) indeterminate for UIP pattern (peribronchovascular and subpleural ground-glass opacities, intermingled with fine reticulation but no honeycombing or traction bronchiectasis). The fourth category, alternative diagnosis, is widely variable, depending on the specific alternative diagnosis, and is not shown. the context of expanding antifibrotic indications; and 7) such testing is not yet widely available. Many also believed that transbronchial forceps biopsy testing needs to be considered at the same time that genomic classifier testing is considered because transbronchial forceps biopsy may have complications (the complications of transbronchial lung biopsy were reported in a previous guideline [2]); in other words, the questions are inseparable. There was consensus that genomic classifier testing e28 should be reconsidered once additional studies are published. Guideline committee vote. The committee’s vote was as follows: strong recommendation for genomic classifier testing, 2 of 34 (6%); conditional recommendation for genomic classifier testing, 12 of 34 (35%); conditional recommendation against genomic classifier testing, 16 of 34 (47%); and strong recommendation against genomic classifier testing, 3 of 34 (12%). One participant abstained from voting because of insufficient expertise. Research needs. The evidence base was notable for imprecision (wide confidence intervals) due to the small study sizes. Additional studies are needed to obtain more exact estimates of sensitivity and specificity. Research is also needed to improve the technique’s sensitivity, assess the downstream consequences of false-negative results (i.e., incorrectly categorizing a patient with the UIP pattern as not having the UIP American Journal of Respiratory and Critical Care Medicine Volume 205 Number 9 | May 1 2022 American Thoracic Society Documents  Lung findings  Cysts (consider LAM, PLCH, LIP, and DIP)  Mosaic attenuation or three-density sign (consider HP)  Predominant GGO (consider HP, smokingrelated disease, drug toxicity, and acute exacerbation of fibrosis)  Profuse centrilobular micronodules (consider HP or smoking-related disease)  Nodules (consider sarcoidosis)  Consolidation (consider organizing pneumonia, etc.)  Mediastinal findings  Pleural plaques (consider asbestosis)  Dilated esophagus (consider CTD) Definition of abbreviations: CT = computed tomography; CTD = connective tissue disease; DIP = desquamative interstitial pneumonia; GGO = ground-glass opacity; HP = hypersensitivity pneumonitis; HRCT = high-resolution computed tomography; ILD = interstitial lung disease; IP = interstitial pneumonia; LAM = lymphangioleiomyomatosis; LIP = lymphoid interstitial pneumonia; NSIP = nonspecific interstitial pneumonia; PLCH = pulmonary Langerhans cell histiocytosis; UIP = usual interstitial pneumonia. The previous term, “early UIP pattern,” has been eliminated to avoid confusion with “interstitial lung abnormalities” described in the text. The term “indeterminate for UIP” has been retained for situations in which the HRCT features do not meet UIP or probable UIP criteria and do not explicitly suggest an alternative diagnosis. Adapted from Reference 2.  CT features of lung fibrosis that do not suggest any specific etiology  Honeycombing with or without traction bronchiectasis/ bronchiolectasis  Presence of irregular thickening of interlobular septa  Usually superimposed with a reticular pattern, mild GGO  May have pulmonary ossification CT features  Reticular pattern with traction bronchiectasis/ bronchiolectasis  May have mild GGO  Absence of subpleural sparing  Peribronchovascular predominant with subpleural sparing (consider NSIP)  Perilymphatic distribution (consider sarcoidosis)  Upper or mid lung (consider fibrotic HP, CTD-ILD, and sarcoidosis)  Subpleural sparing (consider NSIP or smokingrelated IP) Low to very low confidence (<50%)  Subpleural and basal predominant  Subpleural and basal  Diffuse distribution  Often heterogeneous (areas of predominant without subpleural normal lung interspersed with fibrosis)  Often heterogeneous predominance  Occasionally diffuse (areas of normal lung  May be asymmetric interspersed with reticulation and traction bronchiectasis/ bronchiolectasis) Provisional low confidence (51–69%) CT Findings Suggestive of an Alternative Diagnosis Distribution Provisional high confidence (70–89%) Indeterminate for UIP Confident (.90%) Probable UIP Pattern Level of confidence for UIP histology UIP Pattern HRCT Pattern Table 3. High-Resolution Computed Tomography Patterns in Idiopathic Pulmonary Fibrosis AMERICAN THORACIC SOCIETY DOCUMENTS e29 AMERICAN THORACIC SOCIETY DOCUMENTS Histopathology pattern† UIP Probable UIP Indeterminate for UIP or biopsy not performed UIP IPF IPF IPF Non-IPF dx Probable UIP IPF IPF IPF (Likely)‡ Non-IPF dx Indeterminate IPF IPF (Likely)‡ Indeterminate§ Non-IPF dx Alternative diagnosis IPF (Likely)‡ Indeterminate§ Non-IPF dx Non-IPF dx IPF suspected* HRCT pattern Alternative diagnosis Figure 9. Idiopathic pulmonary fibrosis (IPF) diagnosis on the basis of high-resolution computed tomography (HRCT) and biopsy patterns, developed using consensus by discussion. *“Clinically suspected of having IPF” is defined as unexplained patterns of bilateral pulmonary fibrosis on chest radiography or chest computed tomography, bibasilar inspiratory crackles, and age . 60 years. Middle-aged adults (.40 and ,60 yr old) can rarely present with otherwise similar clinical features, especially in patients with features suggesting familial pulmonary fibrosis. † Diagnostic confidence may need to be downgraded if histopathological assessment is based on transbronchial lung cryobiopsy given the smaller biopsy size and greater potential for sampling error compared with surgical lung biopsy. ‡IPF is the likely diagnosis when any of the following features are present: 1) moderate to severe traction bronchiectasis and/or bronchiolectasis (defined as mild traction bronchiectasis and/or bronchiolectasis in four or more lobes, including the lingula as a lobe, or moderate to severe traction bronchiectasis in two or more lobes) in a man .50 years old or in a woman .60 yr old, 2) extensive (.30%) reticulation on HRCT and age . 70 yr, 3) increased neutrophils and/or absence of lymphocytosis in BAL fluid, and 4) multidisciplinary discussion produces a confident diagnosis of IPF. §Indeterminate for IPF 1) without an adequate biopsy remains indeterminate and 2) with an adequate biopsy may be reclassified to a more specific diagnosis after multidisciplinary discussion and/or additional consultation. Adapted from Reference 2. dx = diagnosis; UIP = usual interstitial pneumonia. pattern), and determine the ability of genomic classifier testing to differentiate UIP related to IPF and UIP related to other types of ILD. Diagnostic Approach The committee updated key figures from the 2018 guidelines for diagnosis of IPF (2). The primary change to the diagnostic algorithm is that patients with an HRCT pattern of probable UIP are now managed similarly to patients with UIP, meaning that lung sampling after initial MDD is less likely (Figure 10). The key change to the figure describing combinations of HRCT and histologic patterns is that an HRCT pattern suggestive of an alternative diagnosis combined with a histopathology pattern of probable UIP is now considered indeterminate for IPF rather than non-IPF (Figure 9). The rationale is the committee’s observation that patients with this combination of findings can have heterogeneous patterns of disease behavior and outcomes, including sometimes being similar to patients with IPF; therefore, labeling this as “indeterminate” seems preferable to the more limiting guidance that was provided in the previous guideline (2). e30 Evidence-based Recommendations for Treatment of IPF We suggest not treating patients with IPF with antacid medication for the purpose of improving respiratory outcomes (conditional recommendation, very low quality evidence). Remarks: Antacid medication and other interventions may be appropriate for patients with both IPF and symptoms of gastroesophageal reflux disease (GERD) for the purpose of improving gastroesophageal reflux (GER)–related outcomes in accordance with GER-specific guidelines. Background. Antacid medication was suggested in previous guidelines to improve respiratory outcomes in patients with IPF (1, 3). The recommendations were based on several observations. First, up to 90% of patients with IPF have abnormal acidic GER (80, 81). Second, patients with IPF have a high prevalence of hiatal hernias (82). Third, in theory, microaspiration might worsen IPF. Fourth, a retrospective cohort study reported that antacid therapy was associated with a survival benefit in patients with IPF (83). Finally, another observational study found a modest but statistically significant reduction in the FVC decline and fewer acute exacerbations (84). Since those recommendations were initially formulated, new evidence has been published, so the guideline committee revisited the topic. Summary of evidence. The committee asked, “Should patients with IPF and confirmed GER, with or without symptoms of GERD, be treated with antacid medications to improve respiratory outcomes?” The systematic review that informed the committee’s recommendation is published independently (85); we summarize the salient findings. Five outcomes were designated as critical: disease progression, mortality, exacerbations, hospitalizations, and lung function. Two outcomes were designated as important: GER severity and adverse effects. An initial scoping review identified no studies that specifically analyzed patients with IPF who were stratified as either having or not having confirmed GER to determine the efficacy of antacid medication in these subgroups. Therefore, the search strategy and study selection criteria were broadened, and indirect evidence was sought (i.e., studies that enrolled patients with IPF regardless of whether GER had been confirmed). Fifteen studies were identified that evaluated antacid medication in patients with IPF. The number of participants ranged from 20 to 3,704. American Journal of Respiratory and Critical Care Medicine Volume 205 Number 9 | May 1 2022 AMERICAN THORACIC SOCIETY DOCUMENTS Patient suspected of having IPF Potential cause/associated condition Yes No No Confirmation of specific diagnosis (including with HRCT) Chest HRCT pattern Yes Indeterminate for UIP or alternate diagnosis UIP or probable UIP* MDD BAL† ± TBLC‡ SLB‡ MDD IPF Alternative diagnosis Figure 10. Diagnostic algorithm for idiopathic pulmonary fibrosis (IPF), developed using consensus by discussion. *Patients with a radiological pattern of probable usual interstitial pneumonia (UIP) can receive a diagnosis of IPF after multidisciplinary discussion (MDD) without confirmation by lung biopsy in the appropriate clinical setting (e.g., 60 yr old, male, smoker). BAL may be appropriate in some patients with a probable UIP pattern. †BAL may be performed before MDD in some patients evaluated in experienced centers. ‡Transbronchial lung cryobiopsy (TBLC) may be preferred to surgical lung biopsy (SLB) in centers with appropriate expertise and/or in some patient populations, as described in the text. A subsequent SLB may be justified in some patients with nondiagnostic findings on TBLC. Adapted from Reference 2. HRCT = highresolution computed tomography. Studies included a small, randomized trial that compared the effects of omeprazole and placebo (86), 12 observational studies (4 of which enrolled patients from antifibrotic randomized trials) that compared proton pump inhibitors and/or histamine-2 receptor antagonists with no antacid medication at baseline (83, 84, 87–96), and 2 case series that evaluated proton pump inhibitors and/or histamine-2 receptor antagonists without a control group (80, 97). Ten studies evaluated proton pump inhibitors and/or histamine-2 receptor antagonists (83, 84, 87, 89–92, 94, 96, 97), and the remaining 5 studies evaluated proton pump inhibitors only (80, 86, 88, 93, 95). DISEASE PROGRESSION. When the data from two observational studies were aggregated by meta-analysis, antacid medication had no statistically significant American Thoracic Society Documents effect on disease progression when defined as a composite of .10% decline in FVC, .50-m decline in 6-minute-walk distance (6MWD), or death (91, 92). An observational study of 1,061 patients that was not included in the meta-analysis because it defined disease progression differently showed that antacid medication was not associated with a statistically significant effect on disease progression when defined as a composite of >5% decline in FVC or death; however, it was associated with increased disease progression when defined as a composite of >10% decline in FVC or death (87). MORTALITY. A small randomized trial found no significant difference in 90-day mortality when a proton pump inhibitor was compared with placebo (86), and multiple observational studies that reported mortality at time points ranging from 30 weeks to 5 years all revealed no significant difference when antacid medication was compared with no medication (84, 91, 92, 96). Only the 1-year time point was reported by multiple observational studies and therefore could be evaluated by a meta-analysis, which showed no significant difference when antacid medication was compared with no antacid medication (91, 92, 96). There were similarly no differences in IPF-related mortality according to four observational studies (91–93, 95). EXACERBATIONS AND Meta-analyses of observational studies detected no statistically significant effect on exacerbations over a 30-week to 1-year follow-up period (84, 87) or hospitalizations over a 90-day to 1-year follow-up period (84, 91, 92). A small HOSPITALIZATIONS. e31 AMERICAN THORACIC SOCIETY DOCUMENTS randomized trial similarly showed no effect on hospitalizations at 90 days (86). LUNG FUNCTION. A meta-analysis of three observational studies showed no difference in the change of percentage predicted FVC when patients who received antacid medication were compared with those who did not receive antacid medication (89, 91, 92). Additional observational studies similarly demonstrated no differences in the change in FVC or 6MWD between patients with and without antacid medication over 30 weeks to 1 year (84, 91, 92). A small randomized trial showed that FVC and percentage predicted FVC were both decreased at 90 days in the omeprazole group, but not the placebo group, with no differences in DLCO or 6MWD (86). ADVERSE EFFECTS. One small randomized trial (86) and three observational studies (87, 91, 92) evaluated adverse effects of antacid medication in patients with IPF. In the randomized trial, there was no difference in any adverse effect, severe adverse effects, or specific adverse effects at 90 days (86). Two observational studies looked at specific types of adverse effects and revealed no difference in the antacid medication group compared with the control group at 1 year (91, 92). In the third observational study, there was no difference in the rate of any adverse effect, but there was a higher rate of serious adverse effects in the antacid medication group compared with the control group, although the study had limitations that were acknowledged by its authors (87). QUALITY OF EVIDENCE. The quality of evidence for all outcomes was rated as very low, meaning that the committee should have very low confidence in the estimated effects, and therefore, the effects summarized below should be interpreted with caution. The main reason for the very low quality rating was that the critical outcomes were informed primarily by observational studies, many of which had a risk of immortal time bias. The lone randomized trial was limited by imprecision and short follow-up. Guideline committee conclusions. The pertinent evidence was observational and indirect (i.e., the question was about patients with IPF who had confirmed GER, but the evidence consisted of unselected patients with IPF, both with and without confirmed GER). The committee discussed whether guidance should be provided for patients with IPF plus confirmed GER (i.e., the original question) or for all patients with IPF e32 regardless of whether GER was confirmed or not (i.e., the population for which direct evidence exists), then voted by a two-thirds majority to provide guidance for all patients with IPF regardless of whether GER was confirmed. In the absence of any definitive benefits, the committee voted to make a conditional recommendation against treating patients with IPF with antacid medication for the sole purpose of improving respiratory outcomes. The committee emphasized three things, however. First, it is possible that antacid therapy may have beneficial effects in patients with confirmed GER that were negated by the inclusion of patients with IPF without GER in studies that enrolled all patients with IPF; therefore, the guidance might change if patients with IPF are stratified as either having or not having confirmed GER and the efficacy of antacid medication is determined for each subgroup. Second, the quality of evidence was very low, meaning that the committee had very low confidence in the estimated effects, which should be interpreted with caution. Finally, antacid medication may be indicated in patients with IPF with symptoms of GERD to improve GER-related outcomes, and the committee refers readers to GER-specific clinical practice guidelines. Guideline committee vote. The committee’s vote was as follows: strong recommendation for antacid medication, 0 of 28 (0%); conditional recommendation for antacid medication, 2 of 28 (7%); conditional recommendation against antacid medication, 24 of 28 (86%); and strong recommendation against antacid medication, 2 of 28 (7%). Three participants abstained from voting, 1 citing insufficient evidence and 2 indicating that they believed they had insufficient expertise. Research needs. The predominance of existing evidence is observational and, therefore, susceptible to bias due to unmeasured confounders. Randomized trials comparing the effects of antacid medication and placebo on respiratory outcomes in patients with IPF would be a valuable addition to the field, potentially enabling definitive recommendations. Theoretically, antacid therapy may have a differential effect in patients with confirmed or symptomatic GER, so randomized trials should be powered to look at these subgroups. We suggest not referring patients with IPF for antireflux surgery for the purpose of improving respiratory outcomes (conditional recommendation, very low quality evidence). Remarks: Antireflux surgery may be appropriate for patients with both IPF and symptoms of GERD for the purpose of improving GER-related outcomes in accordance with GER-specific guidelines. Background. Antireflux surgery to improve respiratory outcomes in patients with IPF has never been considered in the context of a clinical practice guideline. Summary of evidence. The committee asked, “Should patients with IPF and confirmed GER, with or without symptoms of GERD, be referred for antireflux surgery to improve respiratory outcomes?” The systematic review that informed the committee’s recommendation is published independently (85); we summarize the salient findings. Five outcomes were designated as critical: disease progression, mortality, exacerbati