AMERICAN THORACIC SOCIETY DOCUMENTS Lymphangioleiomyomatosis Diagnosis and Management: High-Resolution Chest Computed Tomography, Transbronchial Lung Biopsy, and Pleural Disease Management An Official American Thoracic Society/Japanese Respiratory Society Clinical Practice Guideline Nishant Gupta, Geraldine A. Finlay, Robert M. Kotloff, Charlie Strange, Kevin C. Wilson, Lisa R. Young, Angelo M. Taveira-DaSilva, Simon R. Johnson, Vincent Cottin, Steven A. Sahn, Jay H. Ryu, Kuniaki Seyama, Yoshikazu Inoue, Gregory P. Downey, MeiLan K. Han, Thomas V. Colby, Kathryn A. Wikenheiser-Brokamp, Cristopher A. Meyer, Karen Smith, Joel Moss*, and Francis X. McCormack*; on behalf of the ATS Assembly on Clinical Problems THIS OFFICIAL CLINICAL PRACTICE GUIDELINE WAS APPROVED BY THE AMERICAN THORACIC SOCIETY OCTOBER 2017 AND BY THE JAPANESE RESPIRATORY SOCIETY AUGUST 2017 Background: Recommendations regarding key aspects Results: For women who have cystic changes on high-resolution related to the diagnosis and pharmacological treatment of computed tomography of the chest characteristic of LAM, but who have lymphangioleiomyomatosis (LAM) were recently published. We no additional confirmatory features of LAM (i.e., clinical, radiologic, or now provide additional recommendations regarding four specific serologic), the guideline panel made conditional recommendations questions related to the diagnosis of LAM and management of against making a clinical diagnosis of LAM on the basis of the high- pneumothoraces in patients with LAM. resolution computed tomography findings alone and for considering transbronchial lung biopsy as a diagnostic tool. The guideline panel also Methods: Systematic reviews were performed and then discussed made conditional recommendations for offering pleurodesis after an by a multidisciplinary panel. For each intervention, the panel initial pneumothorax rather than postponing the procedure until the considered its confidence in the estimated effects, the balance of fi fi rst recurrence and against pleurodesis being used as a reason to desirable (i.e., bene ts) and undesirable (i.e., harms and burdens) exclude patients from lung transplantation. consequences, patient values and preferences, cost, and feasibility. Evidence-based recommendations were then formulated, written, and Conclusions: Evidence-based recommendations for the diagnosis graded using the GRADE (Grading of Recommendations, Assessment, and treatment of patients with LAM are provided. Frequent Development, and Evaluation) approach. reassessment and updating will be needed. Contents Formulating Questions and Questions and Recommendations Overview Outcomes Question 1 Introduction Literature Search and Study Question 2 Methods Selection Question 3 Committee Composition Evidence Synthesis Question 4 Conflict-of-Interest Development of Conclusions Management Recommendations Guideline Panel Meetings Manuscript Preparation *These authors share joint senior authorship. ORCID ID: 0000-0001-9112-1315 (N.G.). Correspondence and requests for reprints should be addressed to Joel Moss, M.D., Ph.D., Cardiovascular and Pulmonary Branch, NHLBI, National Institutes of Health, Bethesda, MD 20892. E-mail: [email protected] Am J Respir Crit Care Med Vol 196, Iss 10, pp 1337–1348, Nov 15, 2017 Copyright © 2017 by the American Thoracic Society DOI: 10.1164/rccm.201709-1965ST Internet address: www.atsjournals.org American Thoracic Society Documents 1337 AMERICAN THORACIC SOCIETY DOCUMENTS Overview recommendation, low confidence in the believed that the yield of transbronchial estimated effects). lung biopsy likely correlates with This guideline is the continuation of a prior ∘ Remarks: In the guideline panelists’ markers of parenchymal LAM burden lymphangioleiomyomatosis (LAM) clinical practices, a clinical diagnosis of (such as cyst profusion, abnormal guideline document developed by the LAM is based on a combination of diffusing capacity of the lung for carbon American Thoracic Society (ATS) and the characteristic HRCT features plus one monoxide, abnormal FEV1)andthat Japanese Respiratory Society (JRS) (1). or more of the following: presence of appropriate patient selection is required fi The current guideline collates the evidence tuberous sclerosis complex (TSC), to optimize the safety and ef cacy of for emerging advancements in LAM and angiomyolipomas, chylous effusions, this diagnostic approach. Consultation then uses this evidence to formulate lymphangioleiomyomas with an expert center before recommendations pertaining to the (lymphangiomyomas), or elevated undertaking transbronchial lung biopsy, diagnosis and treatment of patients with serum vascular endothelial growth combined with a critical review of the LAM. The intent of the guideline is to factor-D (VEGF-D) greater than or tissue specimens by a pathologist with empower clinicians to apply the equal to 800 pg/ml. expertise in LAM, can help avoid false- d fi recommendations in the context of the When a de nitive diagnosis is required negative test results and the need for a values and preferences of individual in patients who have parenchymal cysts surgical lung biopsy. d patients and to tailor their decisions to the on HRCT that are characteristic of LAM, We suggest that patients with LAM be fi offered ipsilateral pleurodesis after clinical situation at hand. The guideline but no additional con rmatory features their initial pneumothorax rather than panel’s recommendations (Table 1) are of LAM (i.e., clinical, radiologic, or waiting for a recurrent pneumothorax as follows: serologic), we suggest a diagnostic approach that includes transbronchial before intervening with a pleural d Forpatientswhohavecysticchangeson lung biopsy before a surgical lung biopsy symphysis procedure (conditional high-resolution computed tomography (conditional recommendation, very low recommendation, very low confidence (HRCT) of the chest that are confidence in the estimated effects). in the estimated effects). characteristic of LAM, but have no ∘ Remarks: The advantage of ∘ Remarks: This approach is based on the additional confirmatory features of transbronchial lung biopsy is that it high rate of recurrence of spontaneous LAM (i.e., clinical, radiologic, or offers a less-invasive method to obtain pneumothoraces in patients with LAM. serologic), we suggest NOT using the histopathological confirmation of LAM, Nonetheless, the final decision to HRCT features in isolation to make a as compared with surgical lung biopsy. perform pleurodesis and the type of clinical diagnosis of LAM (conditional Although not proven, the panelists pleurodesis (chemical vs. surgical) Table 1. Summary of the Recommendations Provided in This Guideline Strength of Confidence in Context Recommendation Recommendation Estimates of Effect HRCT as sole confirmatory For patients who have cystic changes on HRCT of the Conditional Low feature for LAM diagnosis chest that are characteristic of LAM, but have no additional confirmatory features of LAM (i.e., clinical, radiologic, or serologic), we suggest NOT using the HRCT features in isolation to make a clinical diagnosis of LAM. Transbronchial lung biopsy for When a definitive diagnosis is required in patients who Conditional Very low histopathological diagnosis of have parenchymal cysts on HRCT that are LAM characteristic of LAM, but no additional confirmatory features of LAM (i.e., clinical, radiologic, or serologic), we suggest a diagnostic approach that includes transbronchial lung biopsy before a surgical lung biopsy. Pleurodesis after a sentinel We suggest that patients with LAM be offered Conditional Very low pneumothorax to prevent ipsilateral pleurodesis after their initial recurrence pneumothorax rather than waiting for a recurrent pneumothorax before intervening with a pleural symphysis procedure. Pleurodesis as a contraindication to We suggest that previous unilateral or bilateral pleural Conditional Very low future lung transplant procedures (i.e., pleurodesis or pleurectomy) NOT be considered a contraindication to lung transplantation in patients with LAM. Definition of abbreviations: HRCT = high-resolution computed tomography; LAM = lymphangioleiomyomatosis. 1338 American Journal of Respiratory and Critical Care Medicine Volume 196 Number 10 | November 15 2017 AMERICAN THORACIC SOCIETY DOCUMENTS should be based on shared decision- Methods panel discussed the scope of the document, making between the clinician(s) and the questions to be addressed, the evidence, patient, after education about various Committee Composition and the recommendations. The management options. Every effort must The guideline development panel was co- cosponsoring societies (the ATS and JRS) be made to ensure that the pleurodesis is chaired by F.X.M and J.M. and consisted of provided financial support for the meetings handled by clinicians familiar with clinicians and researchers with recognized and conference calls, as well as travel management of pleural disease in LAM. expertise in LAM (1). A methodologist expenses. Additional support for travel of d We suggest that previous unilateral or (K.C.W.) with expertise in the guideline panelists to meetings was provided by the bilateral pleural procedures development process and application of the not-for-profit LAM Foundation and LAM (i.e., pleurodesis or pleurectomy) NOT Grading of Recommendations, Assessment, Treatment Alliance. The ATS, JRS, and be considered a contraindication to lung Development, and Evaluation (GRADE) Foundations had no influence on question transplantation in patients with LAM approach