AMERICAN THORACIC SOCIETY DOCUMENTS · initial pneumothorax rather than postponing the procedure until the ﬁrst recurrence and against pleurodesis being used as a reason to excludepatients

AMERICAN THORACIC SOCIETYDOCUMENTS

Lymphangioleiomyomatosis Diagnosis and Management:High-Resolution Chest Computed Tomography, Transbronchial LungBiopsy, and Pleural Disease ManagementAn Official American Thoracic Society/Japanese Respiratory Society ClinicalPractice GuidelineNishant 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 aspectsrelated to the diagnosis and pharmacological treatment oflymphangioleiomyomatosis (LAM) were recently published. Wenow provide additional recommendations regarding four specificquestions related to the diagnosis of LAM and management ofpneumothoraces in patients with LAM.

Methods: Systematic reviews were performed and then discussedby a multidisciplinary panel. For each intervention, the panelconsidered its confidence in the estimated effects, the balance ofdesirable (i.e., benefits) and undesirable (i.e., harms and burdens)consequences, patient values and preferences, cost, and feasibility.Evidence-based recommendations were then formulated, written, andgraded using theGRADE (Grading of Recommendations, Assessment,Development, and Evaluation) approach.

Results: For women who have cystic changes on high-resolutioncomputed tomographyof the chest characteristic of LAM,butwhohaveno additional confirmatory features of LAM (i.e., clinical, radiologic, orserologic), the guideline panel made conditional recommendationsagainst making a clinical diagnosis of LAM on the basis of the high-resolution computed tomography findings alone and for consideringtransbronchial lung biopsy as a diagnostic tool. The guideline panel alsomade conditional recommendations for offering pleurodesis after aninitial pneumothorax rather than postponing the procedure until thefirst recurrence and against pleurodesis being used as a reason toexclude patients from lung transplantation.

Conclusions: Evidence-based recommendations for the diagnosisand treatment of patients with LAM are provided. Frequentreassessment and updating will be needed.

ContentsOverviewIntroductionMethods

Committee CompositionConflict-of-InterestManagement

Guideline Panel Meetings

Formulating Questions andOutcomes

Literature Search and StudySelection

Evidence SynthesisDevelopment ofRecommendations

Manuscript Preparation

Questions and RecommendationsQuestion 1Question 2Question 3Question 4

Conclusions

*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 ofHealth, 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

http://orcid.org/0000-0001-9112-1315

mailto:[email protected]

http://10.1164/rccm.201709-1965ST

http://www.atsjournals.org

Overview

This guideline is the continuation of a priorlymphangioleiomyomatosis (LAM)guideline document developed by theAmerican Thoracic Society (ATS) and theJapanese Respiratory Society (JRS) (1).The current guideline collates the evidencefor emerging advancements in LAM andthen uses this evidence to formulaterecommendations pertaining to thediagnosis and treatment of patients withLAM. The intent of the guideline is toempower clinicians to apply therecommendations in the context of thevalues and preferences of individualpatients and to tailor their decisions to theclinical situation at hand. The guidelinepanel’s recommendations (Table 1) areas follows:

d For patients who have cystic changes onhigh-resolution computed tomography(HRCT) of the chest that arecharacteristic of LAM, but have noadditional confirmatory features ofLAM (i.e., clinical, radiologic, orserologic), we suggest NOT using theHRCT features in isolation to make aclinical diagnosis of LAM (conditional

recommendation, low confidence in theestimated effects).∘ Remarks: In the guideline panelists’clinical practices, a clinical diagnosis ofLAM is based on a combination ofcharacteristic HRCT features plus oneor more of the following: presence oftuberous sclerosis complex (TSC),angiomyolipomas, chylous effusions,lymphangioleiomyomas(lymphangiomyomas), or elevatedserum vascular endothelial growthfactor-D (VEGF-D) greater than orequal to 800 pg/ml.

d When a definitive diagnosis is requiredin patients who have parenchymal cystson HRCT that are characteristic of LAM,but no additional confirmatory featuresof LAM (i.e., clinical, radiologic, orserologic), we suggest a diagnosticapproach that includes transbronchiallung biopsy before a surgical lung biopsy(conditional recommendation, very lowconfidence in the estimated effects).∘ Remarks: The advantage oftransbronchial lung biopsy is that itoffers a less-invasive method to obtainhistopathological confirmation of LAM,as compared with surgical lung biopsy.Although not proven, the panelists

believed that the yield of transbronchiallung biopsy likely correlates withmarkers of parenchymal LAM burden(such as cyst profusion, abnormaldiffusing capacity of the lung for carbonmonoxide, abnormal FEV1) and thatappropriate patient selection is requiredto optimize the safety and efficacy ofthis diagnostic approach. Consultationwith an expert center beforeundertaking transbronchial lung biopsy,combined with a critical review of thetissue specimens by a pathologist withexpertise in LAM, can help avoid false-negative test results and the need for asurgical lung biopsy.

d We suggest that patients with LAM beoffered ipsilateral pleurodesis aftertheir initial pneumothorax rather thanwaiting for a recurrent pneumothoraxbefore intervening with a pleuralsymphysis procedure (conditionalrecommendation, very low confidencein the estimated effects).∘ Remarks: This approach is based on thehigh rate of recurrence of spontaneouspneumothoraces in patients with LAM.Nonetheless, the final decision toperform pleurodesis and the type ofpleurodesis (chemical vs. surgical)

Table 1. Summary of the Recommendations Provided in This Guideline

Context RecommendationStrength of

RecommendationConfidence in

Estimates of Effect

HRCT as sole confirmatoryfeature for LAM diagnosis

For patients who have cystic changes on HRCT of thechest that are characteristic of LAM, but have noadditional confirmatory features of LAM (i.e., clinical,radiologic, or serologic), we suggest NOT using theHRCT features in isolation to make a clinicaldiagnosis of LAM.

Conditional Low

Transbronchial lung biopsy forhistopathological diagnosis ofLAM

When a definitive diagnosis is required in patients whohave parenchymal cysts on HRCT that arecharacteristic of LAM, but no additional confirmatoryfeatures of LAM (i.e., clinical, radiologic, orserologic), we suggest a diagnostic approach thatincludes transbronchial lung biopsy before asurgical lung biopsy.

Conditional Very low

Pleurodesis after a sentinelpneumothorax to preventrecurrence

We suggest that patients with LAM be offeredipsilateral pleurodesis after their initialpneumothorax rather than waiting for a recurrentpneumothorax before intervening with a pleuralsymphysis procedure.


Pleurodesis as a contraindication tofuture lung transplant

We suggest that previous unilateral or bilateral pleuralprocedures (i.e., pleurodesis or pleurectomy) NOTbe considered a contraindication to lungtransplantation in patients with LAM.


Definition of abbreviations: HRCT = high-resolution computed tomography; LAM= lymphangioleiomyomatosis.

AMERICAN THORACIC SOCIETY DOCUMENTS

1338 American Journal of Respiratory and Critical Care Medicine Volume 196 Number 10 | November 15 2017

should be based on shared decision-making between the clinician(s) andpatient, after education about variousmanagement options. Every effort mustbe made to ensure that the pleurodesis ishandled by clinicians familiar withmanagement of pleural disease in LAM.

d We suggest that previous unilateral orbilateral pleural procedures(i.e., pleurodesis or pleurectomy) NOTbe considered a contraindication to lungtransplantation in patients with LAM(conditional recommendation, very lowconfidence in the estimated effects).∘ Remarks: Lung transplantation surgeryin patients with a history of priorpleurodesis can be challenging.Patients who have undergone priorpleural procedures (i.e., pleurodesisor pleurectomy) should be referredto a lung transplant team withexpertise in handling complex pleuraldissections.

Introduction

This guideline is the continuation of a priorlymphangioleiomyomatosis (LAM)guideline document developed by the ATSand JRS (1). The current guidelinecollates pertinent evidence and thenuses this evidence to formulaterecommendations pertaining to thediagnosis and management of LAM. Theseguidelines are not intended to impose astandard of care. They provide the basis forrational decisions in the diagnosis andtreatment of LAM. Clinicians, patients,third-party payers, institutional reviewcommittees, other stakeholders, or thecourts should never view theserecommendations as dictates. Noguidelines or recommendations cantake into account the entire, oftencompelling, individual clinicalcircumstances that guide clinical decision-making. Therefore, no one evaluatingclinicians’ actions should attempt toapply the recommendations from theseguidelines by rote or in a blanketfashion. Statements about the underlyingvalues and preferences, as well as qualifyingremarks accompanying eachrecommendation, are integral parts andserve to facilitate more accurateinterpretation; they should never beomitted when quoting or translatingrecommendations from these guidelines.

Methods

Committee CompositionThe guideline development panel was co-chaired by F.X.M and J.M. and consisted ofclinicians and researchers with recognizedexpertise in LAM (1). A methodologist(K.C.W.) with expertise in the guidelinedevelopment process and application of theGrading of Recommendations, Assessment,Development, and Evaluation (GRADE)approach (2) was also a member of thepanel. Patient perspectives were providedby the LAM Foundation (Table 2).

Conflict-of-Interest ManagementGuideline panelists disclosed all potentialconflicts of interest according to ATSpolicies. All conflicts of interest weremanaged by the ATS conflict of interest anddocuments departments using theprocedures described in the previousLAM guidelines (1). All seven membersof the writing group were free of conflictsfor all questions related to this version ofthe guidelines.

Guideline Panel MeetingsSeveral face-to-face meetings,conference calls, and e-mail discussionswere held between 2008 and 2017,during which the guideline development

panel discussed the scope of the document,the questions to be addressed, the evidence,and the recommendations. Thecosponsoring societies (the ATS and JRS)provided financial support for the meetingsand conference calls, as well as travelexpenses. Additional support for travel ofpanelists to meetings was provided by thenot-for-profit LAM Foundation and LAMTreatment Alliance. The ATS, JRS, andFoundations had no influence on questionselection, evidence synthesis, orrecommendations.

Formulating Questions and OutcomesClinical questions were developed,circulated among the panelists, andrated according to clinical relevance.Patient-important outcomes were selecteda priori for each question and categorizedas critical, important, or not important(3). Patient perspectives on the questionsto be addressed were obtained viaquestionnaires distributed by the LAMFoundation.

Literature Search and Study SelectionA detailed description of the search strategywas provided in the recently published LAMguidelines (1). All literature searches wereperformed by a librarian from the NationalInstitute of Health (K.S.), using four

Table 2. Summary of Methodology

Method Yes No

Panel assemblyIncluded experts for relevant clinical disciplines XIncluded individuals who represent the views ofpatients and society at large

X

Included a methodologist with appropriate expertise(documented expertise in conducting systematicreviews to identify the evidence base andthe development of evidence-basedrecommendations)

X

Literature reviewPerformed in collaboration with a librarian XSearched multiple electronic databases XReviewed reference lists of retrieved articles X

Evidence synthesisApplied prespecified inclusion and exclusion criteria XEvaluated studies for sources of bias XExplicitly summarized benefits and harms XUsed PRISMA1 to report systematic review XUsed GRADE to describe quality of evidence X

Generation of recommendationsUsed GRADE to rate the strength ofrecommendations

X

Definition of abbreviations: GRADE =Grading of Recommendations Assessment, Development, andEvaluation; PRISMA1 = Preferred Reporting Items for Systematic Reviews and Meta-analysis 1.



electronic databases: MEDLINE, EMBASE,Web of Science, and Scopus (Table 2). Theliterature search was originally conductedin 2009, subsequently updated in July 2014,July 2015, and May 2016, and includedstudies published before March 2016. Asmaller working group of seven panelists(C.S., F.X.M., G.A.F., K.C.W., N.G., J.M.,and R.M.K.) reviewed the search results andupdated them as necessary.

Evidence SynthesisThe body of evidence for each question wassummarized in collaboration with one of themethodologists (K.C.W.). When possible,data were pooled to derive single estimates.When this was not possible, the range ofresults was reported. The quality of the bodyof evidence was rated using the GRADEapproach (Table 2) (4), as describedpreviously (1).

Development of RecommendationsThe guideline development panelformulated recommendations on thebasis of the evidence synthesis, asdescribed previously (1). Recommendationswere formulated by discussion andconsensus; none of the recommendationsrequired voting. The finalrecommendations were reviewed andapproved by all members of the entirepanel.

The recommendations were ratedas strong or conditional in accordancewith the GRADE approach. The words“we recommend” indicate that therecommendation is strong, whereasthe words “we suggest” indicate thatthe recommendation is conditional.

Table 3 describes the interpretation ofstrong and conditional recommendationsby patients, clinicians, and health carepolicy makers.

Manuscript PreparationThe writing group (C.S., F.X.M., G.A.F.,J.M., K.C.W., N.G., and R.M.K.) drafted thefinal guideline document. The manuscriptwas then reviewed by the entire guidelinedevelopment panel, and their feedback wasincorporated into the final draft. Allmembers of the panel have reviewed thefinal version of the document and approveof the document in its entirety.

Questions andRecommendations

Question 1Should patients be clinically diagnosed withLAM on the basis of their HRCT findingsalone if they have cystic changes in the lungparenchyma that are characteristic of LAMbut have no additional confirmatorycharacteristics of LAM (i.e., clinical,radiologic, or serologic)?

Background. The advent of HRCT ofthe chest has transformed the field of diffusecystic lung diseases. A critical review ofHRCT features can often reveal patterns thatare diagnostic in a significant proportion ofpatients with diffuse cystic lung diseases.The characteristic HRCT pattern of LAM isdefined as the presence of multiple, bilateral,uniform, round, thin-walled cysts present ina diffuse distribution. It has been suggestedthat the diagnosis of LAM can be establishedwith a fair degree of certainty on the basis of

the presence of characteristic HRCT featuresalone (5). However, the rationale forpursuing a definite diagnosis has beenstrengthened of late. A recent randomizedcontrolled trial demonstrated that sirolimusstabilizes lung function decline andimproves quality of life and functionalperformance in patients with LAM (6). Onthe basis of these results, sirolimus is nowU.S. Food and Drug Administrationapproved for treatment of LAM and wasrecommended as the first-line treatmentoption for qualified patients in the previousLAM guideline document (1). However,effective therapy with sirolimus requirescontinuous drug exposure and is associatedwith potential adverse effects. Given thespecter of long-term therapy, it is essentialto have a firm diagnosis before initiatingpharmacotherapy.

Summary of the evidence. Oursystematic review identified three studies thatevaluated the performance characteristics ofHRCTof the chest in establishing the diagnosisof LAM in patients with diffuse cystic lungdiseases (7–9). In all three studies, HRCT ofthe chest from patients with various cysticlung diseases were evaluated, and a diagnosiswas rendered by multiple physicians whowere blinded to clinical and histopathologicalinformation. Clinicians included thoracicradiologists (7–9), pulmonologists (9), andpulmonary fellows (9). Diseases includedLAM (7–9), pulmonary Langerhans cellhistiocytosis (7–9), emphysema (7–9),usual interstitial pneumonia (8), lymphoidinterstitial pneumonia (8, 9), desquamativeinterstitial pneumonia (8), Birt-Hogg-Dubesyndrome (9), amyloidosis (9),hypersensitivity pneumonitis (9), nonspecific

Table 3. Interpretation of Strong and Conditional Recommendations for Stakeholders

Implications for Strong Recommendation Conditional Recommendation

Patients Most individuals in this situation would want therecommended course of action, and only a smallproportion would not.

The majority of individuals in this situation wouldwant the suggested course of action, but manywould not.

Clinicians Most individuals should receive the intervention.Adherence to this recommendation according tothe guideline could be used as a quality criterionor performance indicator. Formal decision aidsare not likely to be needed to help individualsmake decisions consistent with their values andpreferences.

Recognize that different choices will be appropriatefor individual patients and that you must help eachpatient arrive at a management decision consistentwith his or her values and preferences. Decisionaids may be useful in helping individuals to makedecisions consistent with their values andpreferences.

Policy makers The recommendation can be adopted as policy inmost situations.

Policy making will require substantial debate andinvolvement of various stakeholders.



interstitial pneumonia (9), lymphangiomatosis(9), and pleuropulmonary blastoma (9). Twostudies included patients without cystic lungdisease as control subjects, including normalvolunteers and patients with noncysticinterstitial lung diseases (7, 9).

We pooled the data from all threestudies, which included 72 patients withLAM and 141 patients without LAM. Ouranalysis revealed that expert thoracicradiologists diagnosed LAM on the basis ofHRCT review alone with a sensitivity of87.5% and a specificity of 97.5%, indicating afalse-negative rate of 12.5% and a false-positive rate of 2.5%. Assuming that 30% ofpatients who present with cystic lung diseaseof unknown etiology have LAM (1) and thatHRCT has a sensitivity and specificity forLAM of approximately 87% and 97%,respectively, then for every 1,000 patientswith cystic lung disease who undergoHRCT of the chest, 261 patients will becorrectly diagnosed with LAM (true-positive results) and 679 patients will becorrectly determined to not have LAM(true-negative results); however, 21 patientswill be incorrectly diagnosed as havingLAM (false-positive results) and 39 patientswill be incorrectly determined to not haveLAM (false-negative results).

The guideline panel’s confidence in theestimated sensitivity and specificity was low.The studies appropriately compared theHRCT to a gold standard (histopathology);however, confidence was diminished for tworeasons. First, the studies enrolled neitherconsecutive patients nor patients with truediagnostic uncertainty (potential selectionbias). Second, the results may not begeneralizable to facilities that do not haveaccess to an expert thoracic radiologist tointerpret HRCT (indirectness). Supportingthe importance of the latter limitation, theperformance characteristics of pulmonaryphysicians have been shown to be inferior tothoracic radiologists in being able to diagnoseLAM on the basis of HRCT review (9).Third, the studies did not include allpossible causes of cystic lung disease thatcould mimic LAM, such as metastatictumors, light chain deposition disease, etc.Last, isolated cysts have been reported inotherwise asymptomatic, normal individualsand have been postulated to represent anaging manifestation rather than a truepathological disease process (10, 11).

Benefits. The benefit of correctlydiagnosing LAM on the basis of HRCTreview alone is that HRCT of the chest is

noninvasive. If HRCT only could be used tomake the diagnosis of LAM, neithertransbronchial lung biopsy nor surgical lungbiopsy would be required, reducing the riskof complications and the burdens and costsof such procedures.

Harms. False-positive results may leadto missed opportunities to treat the correctdisease as well as the adverse effects andcosts of inappropriate treatment ormanagement of LAM.

Conclusions and researchopportunities. To recommend clinicaldiagnosis of LAM on the basis ofcharacteristic HRCT findings alone, theguideline panel reasoned that the specificitymust be greater than 95%. The rationale wasto minimize false-positive results, becausesuch results lead to missed opportunities totreat the correct disease as well as theadverse effects and costs of inappropriatetreatment and management of LAM. Thespecificity of HRCT achieved theprespecified threshold; however, the panelwas concerned that the specificity wasmisleadingly high because it was derivedfrom referral institutions with thoracicradiologists who have expertise in interstitiallung diseases and could have beensubstantially lower if the studies had beenconducted in different medical centers. Forthis reason, the guideline panel elected tosuggest not making a clinical diagnosis ofLAM on the basis of HRCT findings alone.

The only noninvasive diagnostic testsfor LAM that have been systematicallystudied are HRCT alone and serumVEGF-D. Therefore, research opportunitiesexist to study the sensitivity and specificityof combined findings, such as a HRCT plusclinical features of TSC, angiomyolipoma,chylous effusion, or lymphangioleiomyoma.

Recommendation. For patients whohave cystic changes on HRCT of the chestthat are characteristic of LAM, but have noadditional confirmatory features of LAM(i.e., clinical, radiologic, or serologic), wesuggest NOT using the HRCT features inisolation to make a clinical diagnosis ofLAM (conditional recommendation, lowconfidence in the estimated effects).

Remarks. In the guideline panelists’clinical practices, a clinical diagnosis ofLAM is based on the combination ofcharacteristic HRCT features plus one ormore of the following: presence of TSC,angiomyolipomas, chylous effusions,lymphangioleiomyomas, or elevated serumVEGF-D greater than or equal to 800 pg/ml

(Table 4). In certain cases, such asasymptomatic patients with typical clinicalpresentations for LAM (i.e., young-middleaged, nonsmoking female patients withoutevidence of underlying connective tissuediseases or other features commonly seen incystic lung diseases that can mimic LAM,such as emphysema or Sjogren syndrome)and mild cystic change on HRCT, it may beappropriate to base a probable diagnosis ofLAM on critical review of HRCT alone (5),especially when a definitive diagnosis is notlikely to change management. A secondopinion regarding the diagnosis by anexpert thoracic radiologist can furtherstrengthen confidence in the diagnosis inthese cases. In patients with a probablediagnosis of LAM, the guideline paneliststypically monitor disease progression withserial monitoring of their pulmonaryfunction tests. However, there was generalagreement that a definite diagnosis shouldbe established with one of the additionalcriteria (Table 4) before initiation ofpharmacotherapy with mechanistic targetof rapamycin (mTOR) inhibitors.

Values and preferences. Thisrecommendation places a high value onavoiding missed opportunities to treat thecorrect disease, as well as avoiding theadverse effects and costs of inappropriatetreatment of LAM. It places a lower value onthe potential complications, burdens, andcosts of traditional diagnostic testing.

Question 2Should patients undergo transbronchial lungbiopsy for the diagnosis of LAM if they havecystic changes that are characteristic of LAMon HRCT of the chest but have noadditional confirmatory characteristics ofLAM (i.e., clinical, radiologic, or serologic)?

Background. Typical features onHRCT of the chest can be highly suggestiveof LAM (9). Many experts make a diagnosisof LAM if characteristic cystic lung changeson HRCT are accompanied by thepresence of tuberous sclerosis complex,angiomyolipomas, chylous effusions,lymphangioleiomyomas, or a serum VEGF-Dlevel greater than or equal to 800 pg/ml (5, 12).Although for some patients, such as thosewithout symptoms and a mild cyst burden,a strategy of close monitoring only maybe appropriate, obtaining diagnosticcertainty is the optimal approach in thosewith symptoms or progressive diseasebefore initiating treatment. Video-assistedthoracoscopic surgery (VATS)-guided



surgical lung biopsy has been consideredthe gold standard for obtaininghistopathological confirmation of LAM;however, small retrospective series suggestthat transbronchial lung biopsy can be safeand effective in a proportion of patientswith suspected LAM.

Summary of the evidence. Oursystematic review identified 5 case reports(13–17) and 12 case series (18–29) thatdescribed transbronchial lung biopsy forthe diagnosis of LAM. We did not considerthe case reports due to the high risk ofpublication bias (i.e., patients with

successful outcomes are more likely to besubmitted by clinicians as case reports).Instead, we considered only the caseseries to inform the guideline panel’sjudgments.

The largest relevant case series reportedon 108 Chinese patients with LAM. Thediagnosis was confirmed by lung biopsy in97 patients, including 49 patients who hadbeen diagnosed by transbronchial lungbiopsy. The number of patients who hadundergone transbronchial lung biopsy wasnot reported; however, the diagnostic yieldwould have been 50% if all patients had

undergone transbronchial lung biopsyand higher if fewer had undergonetransbronchial lung biopsy. Thecomplication rate was similarly unreported(29). Four case series provided sufficientcrude data to estimate the diagnostic yieldof transbronchial lung biopsy (23, 24, 28,30). In the largest series, two onlinesurveys were conducted of 1,000 patientswith LAM who were registered with the LAMFoundation. Among the 63 patients whounderwent transbronchial lung biopsy whenthey were initially suspected of having LAM,35 patients (56%) were confirmed to haveLAM by the procedure. The self-reportedcomplication rate from transbronchialbiopsy was approximately 14% (6% withpneumothorax, 4% with bleeding, 2% withchest pain, and 2% with pneumonia) (30).When we pooled the results from the four caseseries, it was determined that 48 out of 81patients (60%) who underwent transbronchiallung biopsy for suspected LAM wereconfirmed to have LAM (23, 24, 28, 30). Ofnote, several series reported that the initialdiagnosis rendered by the local pathologist wasoften nondiagnostic or incorrect and wassubsequently revised to LAM when reviewedby a pathologist with expertise in LAM.

The guideline panel’s judgmentsregarding the utility of transbronchial lungbiopsy in LAM were informed primarily bysmall case series, which provided very lowconfidence in the estimated diagnostic yieldand complication rate. The panel’sconfidence was further lowered by the factthat only a small proportion of patients ineach case series underwent transbronchiallung biopsy, and most of the series did notreport the criteria for patient selection fortransbronchial biopsy; these limitationscollectively increase the possibility of anoverestimated diagnostic yield due toselection bias. The panel speculated that thediagnostic yield varies according to theburden of LAM in the lung. Finally, oneof the larger series relied on patient-reported results.

Benefits. Transbronchial lung biopsyappears to yield a diagnosis of LAM ingreater than 50% of properly selectedpatients with suspected LAM. Definitivediagnosis by transbronchial lung biopsyrenders invasive diagnostic testing, such assurgical lung biopsy, unnecessary.

Harms. Transbronchial lung biopsyis a minimally invasive procedure that maybe associated with bleeding, pneumothorax,or adverse medication effects. The overall

Table 4. Diagnostic Criteria for Lymphangioleiomyomatosis

Definite LAM

Definite diagnosis of LAM can be established if a patient with compatible clinical history* andcharacteristic HRCT of the chest† has one or more of the following features:

1. Presence of TSC‡

2. Renal angiomyolipoma(s)x

3. Elevated serum VEGF-D> 800 pg/ml4. Chylous effusion (pleural or ascites) confirmed by tap and biochemical analysis of the

fluid5. Lymphangioleiomyomas (lymphangiomyomas)x

6. Demonstration of LAM cells or LAM cell clusters on cytological examination of effusionsor lymph nodesjj

7. Histopathological confirmation of LAM by lung biopsy or biopsy of retroperitoneal orpelvic masses

Definition of abbreviations: D2-40 = podoplanin; HMB-45 = human melanoma black-45; HRCT =high-resolution computed tomography; LAM= lymphangioleiomyomatosis; mTOR =mechanistictarget of rapamycin; TSC = tuberous sclerosis complex; VEGF-D = vascular endothelial growthfactor-D; VEGFR3 = vascular endothelial growth factor receptor 3.The diagnosis of LAM should be established using the least invasive approach (details in Figure 1). In somecases, such as asymptomatic patients with mild cystic change on HRCT, a probable diagnosis of LAMwith serial monitoring may be sufficient, if a definite diagnosis will not change management and somelevel of diagnostic uncertainty is acceptable to the patient and clinician. Every effort must be made toestablish a definite diagnosis of LAM before initiation of pharmacological therapy with mTOR inhibitors.*Compatible clinical history with LAM includes young to middle-aged female patients presenting withworsening dyspnea and/or pneumothorax/chylothorax and the absence of features suggestive ofother cystic lung diseases. Typical clues to an alternative etiology of cystic lung disease on historyinclude the presence of sicca symptoms or an underlying diagnosis of connective tissue disease,significant smoking history, personal/family history of non–TSC-related facial skin lesions, and/orkidney tumors. Most patients with LAM will have an obstructive defect on pulmonary function tests.Some patients, especially early in their disease course, may be asymptomatic and have normalpulmonary function tests.†Characteristic HRCT chest features of LAM include the presence of multiple, bilateral, uniform,round, thin-walled cysts present in a diffuse distribution, often with normal-appearing intervening lungparenchyma.‡Detailed history and physical examination to investigate for the presence of TSC is needed. Thediagnosis of TSC is established based on the proposed criteria in the TSC Guidelines (65). Referral toa TSC specialist may be needed if unsure of the diagnosis.xAngiomyolipoma may be diagnosed on the basis of radiographic appearance of characteristicfat-containing lesions either on computed tomography scan or magnetic resonance imaging. Contrast isnot typically required unless the vascular characteristics of the tumor need to be analyzed, such as forevaluation of the potential for hemorrhage or the planning for embolization. Similarly, lymphangioleiomyomascan typically be diagnosed on the basis of characteristic radiographic appearance.jjLAM cell cluster refers to a spherical aggregate of LAM cells enveloped by a layer of lymphaticendothelial cells that is found in chylous effusions of patients with LAM. The diagnosis of LAM can bebased on typical morphological appearance of LAM cells and positive staining for smooth muscle cellmarkers and HMB-45 by immunohistochemistry. Lymphatic endothelial cells surrounding the LAMcells can be highlighted by positive immunohistochemical staining for lymphatic endothelial cellmarkers, including D2-40 and VEGFR-3.



risk of any complication was 14% in thelargest case series that we considered (30)but is generally estimated to be approximately2% (31, 32), which is substantially lessthan the risks associated with a VATS-guided surgical lung biopsy, whichinclude a 1.5 to 4.5% mortality rate and

10 to 19% procedure-related complicationrate (33–36). In theory, patients withcystic diseases such as LAM may be atgreater risk of pneumothorax fromtransbronchial lung biopsy. However, ourevidence synthesis did not support thisconclusion, as the pneumothorax rate of 0 to

6% is comparable to the general population(23, 30).

Conclusion and research opportunities.The guideline panel weighed the estimateddiagnostic yield (50%) versus thecomplication rate (2–14%) and cost ofbronchoscopy and decided that the benefits

Clinical suspicion of LAM1

HRCT chest with featurescharacteristic of LAM2

Detailed clinical evaluation confirms thepresence of TSC3 Confirmed diagnosis of TSC-LAM

Yes

Consider alternative diagnosis

No

Are any of the following present?1. Serum VEGF-D greater than or equal to 800 pg/ml2. Renal AMLs or lymphangioleiomyomas5

3. Positive cytology6

YesConfirmed diagnosis of LAM

No

Is histopathological confirmationdesired/required?7

No Continue close monitoring withserial PFTs every 3–4 months

Yes

Surgical lung biopsy

Confirmed diagnosis of LAM

No

Yes

Transbronchial lung biopsy withcharacteristic features of LAM8

Yes

No

Confirmed diagnosis of LAM

Obtain:1. Serum VEGF-D4

2. Non-contrast CT or MRIabdomen/pelvis5

3. Chylous fluid/node/mass aspiration (if applicable)

Figure 1. Proposed algorithm for the diagnosis oflymphangioleiomyomatosis (LAM) in a patient with compatible clinicalhistory. The algorithm is designed as a step-wise, least-invasive approachto confirm the diagnosis of LAM. Modifications on the basis of clinicaljudgment are frequently required, and diagnostic decisions must beindividualized. AML = angiomyolipoma; CT = computed tomography;DLCO = diffusion capacity of the lung for carbon monoxide; HRCT = high-resolution computed tomography; MRI =magnetic resonance imaging;mTOR =mechanistic target of rapamycin; PFTs = pulmonary functiontests; TSC = tuberous sclerosis complex; VEGF-D = vascular endothelialgrowth factor-D.

1Suspect LAM clinically in young to middle-aged female patientspresenting with worsening dyspnea and/or pneumothorax/chylothorax.Most patients with LAM will have an obstructive defect on PFTs. Somepatients, especially early in their disease course, may be asymptomaticand have normal PFTs.2Characteristic HRCT features of LAM include the presence of multiple,bilateral, round, well-defined, relatively uniform, thin-walled cysts in adiffuse distribution. The intervening lung parenchyma often appearsnormal on HRCT. Other associated features that can be seen on HRCT insome patients with LAM include the presence of: chylous pleural effusion,pneumothorax, ground-glass opacity suggestive of chylous congestion, ormultiple tiny nodules characteristic of multifocal micronodular pneumocytehyperplasia (in patients with TSC-LAM).3Referral to a TSC center should be considered if there is uncertaintyregarding the diagnosis of TSC. Features suggestive of TSC include thepresence of any of the following: subungual fibromas, facialangiofibromas, hypomelanotic macules, confetti lesions, Shagreenpatches, positive family history of TSC, history of seizures or cognitiveimpairment, or presence of cortical dysplasias, subependymal nodules,and/or subependymal giant cell astrocytomas on brain imaging. Routinebrain imaging is not indicated if clinical suspicion for TSC is low. Detaileddiagnostic criteria for TSC to establish a definitive diagnosis have beenpublished (65).4Serum VEGF-D is currently available in the United States as a College ofAmerican Pathologists/Clinical Laboratory Improvement Act–certified testonly through the Translational Trials Laboratory at Cincinnati Children’sHospital Medical Center. Detailed instructions for proper collection,handling, and shipping of VEGF-D specimens are available at thelaboratory website: www.cincinnatichildrens.org/ttdsl.5The diagnosis of AML can usually be made radiographically on the basisof the presence of fat in the tumors. Routine use of contrast is not requiredor recommended for the diagnosis of AMLs. Contrast is useful to definethe aneurysmal burden and other vascular characteristics of the tumor,such as for evaluation of the potential for hemorrhage or planning forembolization. Similarly, lymphangioleiomyomas can typically be diagnosedon the basis of characteristic radiographic appearance.6The sensitivity of cytological analysis of pleural fluid for the diagnosis ofLAM requires further investigation and may only be available at selectcenters. In a majority of patients with chylous effusions, the diagnosis ofLAM can be established on the basis of elevated serum VEGF-D.7The decision to obtain tissue confirmation via invasive means should beindividualized. For some patients with mild disease and a paucity ofsymptoms, a probable clinical diagnosis of LAM with serial monitoring maybe sufficient if a definitive diagnosis of LAM would not changemanagement and some level of diagnostic uncertainty is acceptable to thepatient and the clinician. Every attempt should be made to establish thediagnosis of LAM with certainty before initiation of pharmacologic therapywith mTOR inhibitors.8Transbronchial lung biopsy has an estimated yield of greater than 50%for the diagnosis of LAM, and markers of parenchymal LAM burden suchas abnormal DLCO are associated with an increased diagnostic yield.Transbronchial lung biopsy appears to be safe in LAM on the basis of casereports and small series, but additional studies are required. Consultationwith an expert center is recommended in cases where transbronchialbiopsy is being considered, and for interpretation of the biopsy.



www.cincinnatichildrens.org/ttdsl

of transbronchial lung biopsy outweigh theharms in appropriately selected patients.Generally speaking, we on the guidelinepanel believe that the diagnosis of LAMshould be established in an algorithmicapproach that progresses from the least tomost invasive method required to confirmthe diagnosis of LAM (Table 4 and Figure 1).

Many questions remain unanswered.The diagnostic yield of transbronchial lungbiopsy in an unselected patient populationis unknown and needs to be determined,as does the relationship between diseaseburden and yield. The safety profile oftransbronchial lung biopsy in LAM, especiallypertaining to the risk of pneumothorax,needs to be better understood. The number ofbiopsies that provides the optimal balancebetween diagnostic yield and risk ofcomplications in patients with varyingseverity of LAM needs to be determined. Theuse of endobronchial ultrasound–guidedtransbronchial needle aspiration for thediagnosis of LAM has not been reported butmay be an attractive option in patientswith LAM who have mediastinal or hilaradenopathy, if studies demonstrate areasonable yield and safety profile. Finally,the safety and efficacy of transbronchial lungcryobiopsy needs to be better understoodfor patients with suspected LAM (37).

The decision to obtain lung biopsy(transbronchial or surgical) for tissuediagnosis should be individualized for everypatient. For some patients with mild diseaseand a paucity of symptoms, serialmonitoring may be sufficient, especially ifsome level of diagnostic uncertainty isacceptable to the patient and clinician and adefinite diagnosis is unlikely to changemanagement. In contrast, VATS-guidedsurgical lung biopsy may be moreappropriate for patients with a low cystburden, given the potential for samplingerror associated with transbronchial lungbiopsy. Computed tomography can be usedto guide lesion-targeted transbronchial lungbiopsy on the basis of distribution ofparenchymal abnormalities. In addition, theclinician should take into consideration thatthe pathological diagnosis of LAM cansometimes be made by less-invasive means,such as by demonstration of LAM cellclusters in chylous effusions (38, 39) oraspirates or core biopsies of pulmonaryor extrapulmonary lymph nodes ormasses (28, 40–42). The performancecharacteristics and diagnostic yield of thesemethodologies, however, is not well

established and needs to be studied.Consultation with expert LAM centers isadvised to individualize the approach todiagnosis in complex patients. On occasion,re-review of archival tissues from priorprocedures by expert pathologists canreveal the diagnosis of LAM and obviate theneed for biopsy. Examples include lungtissue obtained from prior bleb resectionsfor pneumothorax or uterine and adnexaltissues from prior hysterectomies. Everyattempt should be made to establish thediagnosis of LAM with certainty beforeinitiation of pharmacologic therapy withmTOR inhibitors.

Recommendation. When a definitivediagnosis is required in patients who haveparenchymal cysts on HRCT that arecharacteristic of LAM, but no additionalconfirmatory features of LAM (i.e., clinical,radiologic, or serologic), we suggest adiagnostic approach that includestransbronchial lung biopsy before a surgicallung biopsy (conditional recommendation,very low confidence in the estimated effects).

Remarks. The advantage oftransbronchial lung biopsy is that it offersa less-invasive method to obtainhistopathological confirmation of LAM, ascompared with surgical lung biopsy. Althoughnot proven, the panelists believed that the yieldof transbronchial lung biopsy likely correlateswith markers of parenchymal LAM burden(such as cyst profusion, abnormal diffusingcapacity of the lung for carbon monoxide[DLCO], abnormal FEV1) and thatappropriate patient selection is required tooptimize the safety and efficacy of thisdiagnostic approach. A recent studyevaluating the role of transbronchial lungbiopsy in 24 consecutive patients presentingto a LAM Clinic revealed a diagnostic yield of71%, which was inversely correlated withDLCO (43). Consultation with an expertcenter before undertaking transbronchial lungbiopsy, combined with a critical review of thetissue specimens by a pathologist withexpertise in LAM, can help avoid false-negative test results and the need for asurgical lung biopsy.

Values and preferences. Thisrecommendation places a high value on therisk reduction and cost savings of the less-invasive and less-expensive approach oftransbronchial lung biopsy as opposed to aVATS-guided surgical lung biopsy. It placesa lower value on the desire to confirm thediagnosis with a single diagnostic test.

Question 3Should patients with LAM undergoipsilateral pleurodesis after an initialpneumothorax or wait for a recurrencebefore intervening with a pleural symphysisprocedure?

Background. LAM is characterized byan increased risk of recurrent spontaneouspneumothoraces. On the basis of the highrisk of recurrence in patients with LAM, anexpert panel supported pleurodesis after thefirst episode of pneumothorax in patientswith LAM (44).

Summary of the evidence. Oursystematic review did not identify anystudies that compared outcomes amongpatients with LAM who underwentpleurodesis after an initial pneumothoraxversus those who underwent pleurodesisafter a recurrent pneumothorax. The panel,therefore, used seven case series thatreported the incidence of pneumothoracesamong patients with LAM (19, 21, 28, 29,44–48) and two observational studies thatalso compared the incidence of recurrentpneumothorax among those who hadundergone pleurodesis to those who hadnot (44, 46) to inform the guideline panel’sjudgments.

Pooling data demonstrated thatpneumothorax occurred in 902 out of 1,591(57%) patients with LAM (19, 21, 28, 29,44–48). Recurrences were common, withestimates ranging from 29 to 81%, althoughmost estimates were around 70% (28, 29,44, 46, 48). Patients frequently had multiplerecurrences, with estimates ranging from3.2 to 5.0 pneumothoraces per patient inthe pneumothorax-affected groups (21, 44,45). The observational studies found thatapproximately 65% of patients who weremanaged conservatively after theirinitial pneumothorax had recurrentpneumothoraces, compared with only 18 to32% of patients who had pleurodesis(44, 46). The rate of complications due topleurodesis was not reported. The guidelinepanel had very low confidence in theestimated incidence of pneumothoracesin patients with LAM because theyderived from case series and smallobservational studies.

With multiple recurrentpneumothoraces per patient, the cost oftreatment of pneumothoraces can besubstantial. In one series, the average timespent in the hospital due to pneumothoraceswas approximately 1 month per patient,



which was associated with substantial costsdue to hospital expenses and lostproductivity (44).

Benefits. Early pleurodesis after aninitial pneumothorax decreases the risk ofrecurrent pneumothoraces, therebydecreasing morbidity, burden, and cost.

Harms. Pleurodesis is an invasiveprocedure associated with pain andpotential complications. Prior pleurodesismay also be weighed when consideringfuture candidacy for lung transplant.

Conclusions and researchopportunities. The guideline panel weighedthe desirable consequences of performingpleurodesis after an initial pneumothorax(i.e., a roughly 30–45% lower risk of recurrentpneumothorax and overall cost savings)against the undesirable consequences(i.e., pain, potential complications, impact oncandidacy of transplantation) and decidedthat the balance favors pleurodesis. Amongthe panel’s considerations was the fact thatthe undesirable consequences of pleurodesisare merely delayed rather than avoided,because most patients will eventually suffer arecurrent pneumothorax and requirepleurodesis.

There are multiple ways to performpleurodesis, each with its own set ofadvantages and disadvantages. Generallyspeaking, pleurodesis can either be achievedby chemical instillation of a sclerosing agentvia a chest tube or by surgical means usingmechanical abrasion, talc poudrage, orpleurectomy. Although talc is the mostcommon sclerosant used for pleurodesis, otheragents, such as tetracycline derivatives, silvernitrate, iodopovidone, and bleomycin, havebeen used with varying degrees of success(49–51). In practice, the panelists generallyuse mechanical abrasion with an earnestattempt to address the entire parietal pleuralsurface for the initial pneumothorax andreserve more aggressive approaches, such astalc poudrage and pleurectomy, for recurrentand refractory pneumothoraces. Theimportance of knowledge and priorexperience in management of pleural diseasein LAM cannot be overstated, and pleuralcomplications in LAM are best handled bythoracic surgeons with expertise in managingpatients with LAM.

The ideal method of achieving pleuralsymphysis in patients with LAM, one thatprovides the optimal balance betweenefficacy of preventing future recurrences andthe least risk of intra- and postoperativecomplications during lung transplantation,

is not clear. The efficacy of alternative meansof achieving pleurodesis, such as total pleuralcovering, whichmay prevent adhesions and theassociated surgical complications duringtransplant (52), and autologous blood patchpleurodesis, which is associated withsignificantly less pain as compared with thetraditional means of achieving pleuralsymphysis (53), needs to be studied in patientswith LAM. In addition, a better understandingof pneumothoraces and their impact on long-term disease outcomes needs to be established.With the recognition of mTOR inhibitors aseffective therapeutic agents for patients withLAM, the impact and role of mTOR inhibitionon pneumothorax occurrence and recurrenceneeds to be assessed.

Recommendation. We suggest thatpatients with LAM be offered ipsilateralpleurodesis after their initial pneumothoraxrather than waiting for a recurrentpneumothorax before intervening with apleural symphysis procedure (conditionalrecommendation, very low confidence in theestimated effects).

Remarks. This approach is based onthe high rate of recurrence of spontaneouspneumothoraces in patients with LAM.Nonetheless, the final decision to performpleurodesis and the type of pleurodesis(chemical vs. surgical) should be based onshared decision-making between theclinician(s) and patient, after educationabout various management options. Lungbiopsy at the time of pleurodesis forpneumothorax may be useful in selectedpatients who do not already have aconfirmed diagnosis of LAM but can beassociated with added risk (e.g., prolongedair leak and chronic bronchopleural fistulaformation) (54) and should only be usedwhen ATS/European Respiratory Societydiagnostic criteria for LAM are nototherwise met and a histologic diagnosis isabsolutely necessary. Every effort must bemade to ensure that the pleurodesis ishandled by clinicians familiar withmanagement of pleural disease in LAM.

Values and preferences. Thisrecommendation places a high value onreduction in the morbidity and cost associatedwith a recurrent pneumothorax. It places lowervalue on the adverse effects of pleurodesis.

Question 4Should patients with LAM who have had aprior pleural intervention (either pleurodesisor pleurectomy) be excluded fromconsideration for lung transplantation?

Background. LAM typically progressesand may ultimately lead to respiratoryinsufficiency if it is left untreated. Lungtransplantation remains the only treatmentmodality available for patients with end-stagelung disease due to LAM. A significantproportion of patients with LAM who presentfor transplant evaluation have undergone priorunilateral or bilateral pleurodesis procedures.These pleural interventions can increase therisk of bleeding complications at the time oflung transplantation, and some centersconsider bilateral pleurodesis to be a relativecontraindication to lung transplantation (48).

Summary of the evidence. Oursystematic review identified fiveobservational studies that enrolled patientswith LAM undergoing lung transplantationand compared outcomes among those whohad previous pleurodesis or pleurectomyversus those who did not (44, 55–58). Inaddition, five case series were found thatdescribed outcomes of lung transplantationfor LAM but did not compare outcomesamong patients with and without priorpleural procedure (59–63). Two of the caseseries were published in foreign languagesand, therefore, were not considered (62, 63).

The observational studies collectivelyincluded 182 patients with LAM who wereundergoing lung transplantation. Thisincluded 31 patients (17%) who hadundergone unilateral pleurodesis, 55patients (30%) who had undergone bilateralpleurodesis, 10 patients (5%) who hadundergone unilateral pleurectomy, 7patients (4%) who had undergone bilateralpleurectomy, and 79 patients (43%) who hadnot undergone a previous pleural procedure.Patients who had undergone a previouspleural procedure were more likely to haveintra- or postoperative hemorrhage (48% vs.7%; relative risk, 6.46; 95% confidence interval,2.44–17.11) (44, 56, 57), and there was atrend toward such patients being more likelyto have pleural adhesions (65% vs. 46%;relative risk, 1.42; 95% confidence interval,0.96–2.12) (55, 56, 58). However, there wasno significant difference in the length ofhospital stay (44), lung function (58),mortality (58), or risk of chylous effusions(58). The guideline panel had very lowconfidence in these estimated outcomes,because the data were derived from smallobservational studies.

For general pulmonary populations,the International Society for Heart andLung Transplantation Guidelinecommittee recently recommended that



pleurodesis not be considered acontraindication to lung transplantationand that a pneumothorax in a potentialfuture transplant recipient should be giventhe best immediate management withoutundue concern that the choice ofintervention will influence futureacceptance for transplantation (64). Therisks associated with transplantation ofpatients with prior bilateral pleurodesiswere not directly addressed in thisconsensus document, however.

Benefits. Allowing patients with LAMwho have had prior pleural proceduresto undergo lung transplantation confersall of the potential advantages of lungtransplantation in a patient with end-stagelung disease, including improved lungfunction and increased survival (55).

Harms. Prior pleural proceduresincrease the risk of intra- and postoperativebleeding and prolong operative time,although other outcomes are the same asthose seen in patients who have not had aprior pleural procedure.

Conclusion and research opportunities.The guideline panel weighed the desirableconsequences of allowing a patient to beconsidered for lung transplantation (i.e., hopeand, for those who undergo transplant,improved lung function and increasedsurvival) against the undesirable consequences(i.e., more likely to have intra- andpostoperative bleeding) and determined thatthe balance favors lung transplantation.

Among the panel’s considerations was thefact that the undesirable consequences aregenerally short term and rarely fatal, whereasthe potential benefits are longer lasting andlife-saving.

An unanswered question regardinglung transplantation in LAM is thedifference in outcomes after a bilateral lungtransplant compared with a single lungtransplant. This is especially important,because if there is no difference in outcomesafter a single lung transplant, then somepatients with prior unilateral pleurodesismay electively undergo single lungtransplantation on the contralateral sideand potentially avoid the bleedingcomplications associated with thetransplant.

Recommendations. We suggest thatprevious unilateral or bilateral pleuralprocedures (i.e., pleurodesis orpleurectomy) NOT be considered acontraindication to lung transplantationin patients with LAM (conditionalrecommendation, very low confidence in theestimated effects).

Remarks. Lung transplantationsurgery in patients with a history ofprior pleurodesis can be challenging.Patients who have undergone priorpleural procedures should be referredto a lung transplant team with expertisein handling complex pleural dissections.

Values and preferences. Thisrecommendation places a high value

on the later benefits of lung transplantationand a lower value on surgical complications.

Conclusions

The guideline panel used comprehensiveevidence syntheses to inform its judgmentsregarding the balance of benefits versusburdens, adverse effects, and costs; the qualityof evidence; the feasibility; and theacceptability of various interventions. Forwomen who have cystic changes on HRCT ofthe chest characteristic of LAM, but who haveno additional confirmatory features ofLAM (i.e., clinical, radiologic, or serologic),the guideline panel made conditionalrecommendations against making a clinicaldiagnosis of LAM on the basis of the HRCTfindings alone and for consideringtransbronchial lung biopsy as a diagnostictool. The guideline panel also madeconditional recommendations for offeringpleurodesis after an initial pneumothoraxrather than waiting for a recurrentpneumothorax and against pleurodesisbeing used as a reason to exclude patientsfrom lung transplantation. Clinicians facedwith making management decisions forpatients with LAM should individualizetheir decisions, because the evidence baseprovided insufficient confidence in theestimated effects to warrant strongrecommendations for or against anyintervention. n

This official clinical practice guideline was prepared by an ad hoc subcommittee of the ATS Assembly on Clinical Problems.

Members of the Writing Group are as follows:

FRANCIS X. MCCORMACK, M.D. (Co-Chair)JOEL MOSS, M.D., PH.D. (Co-Chair)NISHANT GUPTA, M.D., M.S.GERALDINE A. FINLAY, M.D.ROBERT M. KOTLOFF, M.D.CHARLIE STRANGE, M.D.KEVIN C. WILSON, M.D.

Members of the subcommittee are as follows:

FRANCIS X. MCCORMACK, M.D. (Co-Chair)JOEL MOSS, M.D., PH.D. (Co-Chair)THOMAS V. COLBY, M.D.VINCENT COTTIN, M.D.GREGORY P. DOWNEY, M.D.GERALDINE A. FINLAY, M.D.NISHANT GUPTA, M.D., M.S.MEILAN K. HAN, M.D.YOSHIKAZU INOUE, M.D., PH.D.

SIMON R. JOHNSON, M.D.ROBERT M. KOTLOFF, M.D.CRISTOPHER A. MEYER, M.D.JAY H. RYU, M.D.STEVEN A. SAHN, M.D.KUNIAKI SEYAMA, M.D., PH.D.KAREN SMITH, M.L.S.CHARLIE STRANGE, M.D.ANGELO M. TAVEIRA-DASILVA, M.D., PH.D.KATHRYN A.WIKENHEISER-BROKAMP, M.D., PH.D.KEVIN C. WILSON, M.D.LISA R. YOUNG, M.D.

Author Disclosures: F.X.M. holds a patentfor the use of VEGF-D in the diagnosis oflymphangioleiomyomatosis, served as aconsultant for LAM Therapeutics, andserved on a data and safety monitoringboard for Takeda. V.C. served as a speakerfor Sanofi-Aventis U.S.; served on a dataand safety monitoring board for Promedior;served as a speaker and consultant for and

received travel support from BoehringerIngelheim International, F. Hoffmann-LaRoche, and Novartis; and receivedhonoraria for an adjudication committeefrom Gilead Sciences; and his spouse ownsstocks, stock options, or other ownershipsinterests in Sanofi-Aventis U.S. M.K.H.served as a speaker and consultant for andreceived research support from NovartisPharma; served as a consultant forAstraZeneca, Boehringer IngelheimInternational, GlaxoSmithKline, andSunovion; and served as a speaker forBoehringer Ingelheim International. S.R.J.served on an advisory committee for Pfizer,received research support from LAMTherapeutics, and served as a speaker forNovartis. S.A.S. served on a steeringcommittee for InterMune and served as aclinical investigator for Actelion, Arresto,Celgene, and Gilead. C.S. served as aconsultant for AstraZenecaPharmaceuticals; served on a data safetyand monitoring board for Arrowhead



Pharmaceuticals; received researchsupport from Adverum, CSL Behring,Novartis, Pulmonx Corporation, and Shire;served as a consultant, on an advisorycommittee, and received research support

from BTG International; served as aconsultant and received research supportfrom Grifols Therapeutics; and ownsstocks, stock options, or other ownershipsinterests in Abeona. J.M., T.V.C., G.P.D.,

G.A.F., N.G., Y.I., R.M.K., C.A.M., J.H.R.,K. Seyama, K. Smith, A.M.T.-D., K.A.W.-B.,K.C.W., and L.R.Y. reported norelationships with relevant commercialinterests.

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