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Division of Pulmonary and Critical Care Medicine, Mayo Clinic, Rochester, Minnesota
Pulmonary-Critical Care Medicine Branch, and Biostatistics Research Branch, Division of Epidemiology and Clinical Applications, National Heart, Lung, and Blood Institute
Division of Lung Diseases, National Heart, Lung, and Blood Institute Project Office
Department of Diagnostic Radiology, Warren G. Magnuson Clinical Center, National Institutes of Health, Bethesda, MD
Departments of Quantitative Health Sciences and Critical Care and Pulmonary Medicine, Cleveland Clinic Foundation, Cleveland
Division of Pulmonary and Critical Care Medicine, University of Cincinnati, Cincinnati, Ohio
National Jewish Medical and Research Center, Denver, Colorado
Pulmonary and Critical Care Division, New England Medical Center, Boston, Massachusetts
Division of Pulmonary and Critical Care Medicine, Stanford University Medical Center, Stanford, California
CIGNA HealthCare, Bloomfield, Connecticut
ABSTRACT
Rationale: Pulmonary lymphangioleiomyomatosis is a progressive cystic lung disease that is associated with infiltration of atypical smooth muscle–like cells. Previous descriptions of clinical characteristics of subjects with lymphangioleiomyomatosis have been based on a limited number of patients.
Objectives: To describe the clinical characteristics of subjects with pulmonary lymphangioleiomyomatosis, both sporadic and tuberous sclerosis–related forms.
Methods: Over a 3-yr period, from 1998 to 2001, 243 subjects with pulmonary lymphangioleiomyomatosis were enrolled into a national registry; 13 subjects who had already undergone lung transplantation were excluded for the purposes of this report.
Measurements and Main Results: All 230 subjects were women, aged 18 to 76 yr (mean ± SE, 44.5 ± 0.65 yr). The average age at onset of symptoms was 38.9 ± 0.73 yr and at diagnosis was 41.0 ± 0.65 yr. Tuberous sclerosis complex was present in 14.8% of subjects. Pulmonary manifestations, most commonly spontaneous pneumothorax, were the primary events leading to the diagnosis in 86.5% of cases. Nearly 55% of the subjects were being treated with a progesterone derivative. An obstructive pattern on pulmonary function testing was observed in 57.3% of the subjects, whereas 33.9% had normal spirometric results. Women with tuberous sclerosis–related lymphangioleiomyomatosis were younger and had less impaired lung function compared with those with the sporadic form.
Conclusions: The age range of women afflicted with pulmonary lymphangioleiomyomatosis is broader than previously appreciated and the degree of pulmonary function can be quite variable, with one-third of subjects having normal spirometry at enrollment into this registry.
Key Words: lymphangioleiomyomatosis registry tuberous sclerosis
Pulmonary lymphangioleiomyomatosis (LAM) is a relatively rare disorder that affects almost exclusively women, primarily in their reproductive years (1–8). It is characterized by proliferation of atypical smooth muscle–like cells with associated cystic changes in the lung. This destructive lung process is progressive and may result in respiratory failure with pneumothorax and chylous pleural effusion as well-recognized complications.
Lymphangioleiomyomatosis also occurs in subjects with tuberous sclerosis complex (TSC), an autosomal dominant neurocutaneous syndrome with a shared molecular etiology. TSC is associated with hamartoma formation in multiple organ systems, including the central nervous system, the skin, the eye, the abdominal viscera (especially the kidney), and the lung. Most patients who seek medical attention for LAM, however, have a sporadic form of the disease (sporadic LAM) unassociated with germ-line mutations in TSC genes. Patients with sporadic LAM may have some of the extrapulmonary manifestations that are found in TSC, including renal angiomyolipomas, axial lymphadenopathy and abdominal lymphangiomyomas, but they do not have the skin, central nervous system, and eye manifestations that are required for the diagnosis of TSC based on the modified Gomez criteria (1–3, 9). Whereas biopsy-documented LAM has been reported in a few men with TSC (10), pulmonary involvement with sporadic LAM is seen exclusively in women (11–13).
In 1997, a national LAM registry was established by National Heart, Lung, and Blood Institute (NHLBI) to more accurately characterize the demographic, clinical, physiologic, and radiologic features of subjects with LAM. This study was not designed to answer the question of efficacy of therapy. Additional aims for this registry included collection of tissue from participants to set the stage for future studies into the molecular basis of LAM and to possibly use the assembled cohort to conduct future clinical trials. This article outlines the baseline characteristics of subjects with LAM, both sporadic and TSC-related forms, at the time of enrollment in the LAM registry.
METHODS
Study Design
The LAM registry was organized as follows: (1) a steering committee, (2) clinical centers, (3) a data coordinating center, (4) the NHLBI project office, and (5) a data and safety monitoring board. This registry study was divided into three phases: phase I, design and development; phase II, recruitment and data collection; and phase III, data analysis and closure (14). During phase II, subjects returned annually for follow-up visits.
Study Subjects
Two hundred and forty-three subjects with LAM were enrolled between August 1998 and October 2001 through six participating clinical centers: the Cleveland Clinic Foundation (Cleveland, OH), the Mayo Clinic (Rochester, MN), the National Institutes of Health (NHLBI, Bethesda, MD), the National Jewish Medical and Research Center (Denver, CO), the New England Medical Center (Boston, MA), and the Stanford University Medical Center (Palo Alto, CA). The registry protocol was approved by their respective appropriate institutional review boards and each subject signed an informed consent. Inclusion criteria included a clinically definite diagnosis of LAM and willingness to return for follow-up once per year. All patients with a diagnosis of sporadic LAM or TSC-LAM, whether they (1) had been previously seen and diagnosed, (2) were regularly seen, or (3) were newly referred to each center, were offered the opportunity to participate in the study. Therefore, both prevalent (subjects with previously diagnosed sporadic LAM or TSC-LAM) and incident (new diagnoses) cases were enrolled. New subjects were recruited through the referral networks of each clinical center, TSC clinics (source of most patients with TSC-LAM), postings on the web, publication of a description of the LAM registry in journals, and advertisement in the newsletters of the LAM Foundation (Cincinnati, OH) and the Tuberous Sclerosis Alliance (Silver Spring, MD).
One hundred and twenty-five patients (51.4%) were included in a previous publication describing the correlation between maximal oxygen uptake and the severity of disease in LAM authored by the NHLBI group (15). Thirteen patients had already undergone lung transplantation at the time of enrollment. For the purposes of this study, these 13 lung transplant recipients were excluded. The remaining 230 subjects were analyzed for this report.
Diagnostic Criteria
All pathologic specimens and high-resolution computed tomographic (HRCT) studies were reviewed by expert panels, with the diagnosis of LAM confirmed by at least one of the following criteria: (1) lung biopsy (n = 125), (2) biopsy of lymph node or other mass (n = 21), or (3) HRCT scan of the chest judged to be diagnostic of LAM with a high degree of certainty (16) by two of the three expert radiologists (n = 84). Among 84 patients (62 sporadic and 22 patients with TSC-LAM) diagnosed by HRCT, 51 patients (60.7%) had renal angiomyolipomas, chylothorax, and/or TSC; the remaining 33 patients were diagnosed by HRCT lung parenchymal changes alone.
The LAM registry enrolled patients with both the sporadic form of LAM as well as those with underlying TSC.
Pulmonary Function Methodology
Pulmonary function testing was reviewed by an expert panel. The minimum data collected for the study included spirometry performed before and after the inhalation of a bronchodilator. When available, lung volume measurements, single-breath diffusing capacity, and arterial blood gases were also collected.
Acceptability and reproducibility criteria from the latest American Thoracic Society recommendations for standardization were used to judge the validity of each testing session (17–20). American Thoracic Society standards for acceptability and reproducibility criteria were also used for the single-breath diffusing capacity test (18). Percentage of predicted values reported in this article used the following reference equations: spirometry (reference equations of Hankinson and coworkers [21]), lung volumes (reference equations of Crapo and coworkers [22]), and diffusing capacity (nonsmoker reference equations of Miller and coworkers [23]). Bronchodilator response is defined as increase in FEV1 of at least 12% and 200 ml.
Spirometry (before and after the inhalation of a bronchodilator) and diffusing capacity data were acceptable in 217 patients. The 13 remaining patients had a persistent pneumothorax at the time of their initial visit or refused bronchodilator administration.
Quality-of-Life Instruments
The short form (SF)-36 is a multipurpose, short-form health survey with 36 questions (24). The SF-36 standardized scoring system yields a profile of eight health scores, two summary measures (physical and mental health), and a self-evaluated change in health status.
The St. George's Respiratory Questionnaire (SGRQ) is a self- administered health-related quality-of-life measure for patients with respiratory disease (25).
Statistical Analysis
Comparisons of percentages for sporadic LAM versus TSC-LAM patients were made with the 2 test or Fisher's exact test. Means of continuous variables were compared between groups with a two-sample t test. Pearson correlations were used to measure association between SF-36 quality-of-life scales and baseline spirometry and diffusion capacity. Because not all measurements were available for all subjects, the sample sizes differ somewhat for different results. All p values reported correspond to two-sided tests. Analyses were performed with the SAS version 8.2 software packages (SAS Institute, Inc., Cary, NC).
All data in RESULTS are expressed as means ± SE unless specified otherwise.
RESULTS
Demographic Data
All enrolled subjects were women; only 2.6% were current smokers (Table 1). Mean age at enrollment was 44.5 ± 0.65 yr (mean ± SE); range, 18 to 76 yr. Nearly 40% were postmenopausal (natural or oophorectomy-related menopause) at enrollment, including 27% (of 230 subjects) on the basis of oophorectomy. The mean age at menopause was 41.7 ± 0.76 yr. Thirty-four subjects (14.8%) had underlying TSC.
Spontaneous pneumothorax was the sentinel event leading to the diagnosis of LAM in about one-third of patients, and together with other pulmonary symptoms, including shortness of breath or wheezing, was the primary presentation in 64.2% of cases (Table 1). Abnormal chest radiograph or the presence of pleural effusion was the initial manifestation in an additional 22.3%.
Clinical Characteristics
At enrollment, the most common symptom was breathlessness (Table 2). Pneumothorax had previously occurred in 55.5%; the mean number of pneumothoraces in subjects that had had at least one pneumothorax was 4.4 ± 0.53. Of those with a history of pneumothorax, 4.8% had experienced an episode related to air travel. Medical or surgical pleurodesis had been performed in 44.3%; 16.1% of all subjects had undergone bilateral pleurodesis. Subjects with TSC-LAM had a significantly higher prevalence of renal angiomyolipomas and had undergone a nephrectomy more commonly compared with those with sporadic LAM.
Two-thirds of subjects had been pregnant. Of 353 pregnancies, 66.9% had resulted in live birth, 16.7% spontaneous abortion, 15.0% therapeutic abortion, and 1.4% in stillbirth. Twenty-five patients (21.7% of those who had been pregnant and able to recall symptoms) had experienced worsening of respiratory symptoms during pregnancy.
Nearly 55% of subjects were being treated with a progesterone derivative at the time of enrollment (Table 2), more often in those with sporadic LAM compared with those with TSC-LAM. Nearly one-third of the subjects were receiving supplemental oxygen therapy, at least part time.
Lung Function
Baseline pulmonary function data of the LAM registry participants are shown in Tables 3 and 4 and in Table E1 (see the online supplement). Spirometric evidence of airflow limitation was the most common pulmonary function abnormality and was followed by a reduced diffusing capacity. Spirometric results were normal in 33.9% of subjects. When compared with subjects with sporadic LAM, those with TSC-LAM more often had normal spirometry and diffusing capacity.
Laboratory Results
Laboratory results including complete blood count, serum chemistries, and liver enzyme levels, and urinalysis revealed no abnormalities that were judged to be informative. Hypoxemia on room air at rest as defined by PaO2 55 mm Hg or SaO2 88% was noted in 6.2 and 4.2% of all subjects with available data, respectively (Table 5).
Quality of Life
The physical and mental component scores (mean ± SE) of the SF-36 quality of life for LAM registry patients were 39.7 ± 0.82 and 50.2 ± 0.66, respectively, at baseline (see Figure E1). They are quite similar to those in other specific normative populations with chronic lung disease (42.3 ± 1.05 and 44.5 ± 0.91, physical and mental scores, respectively) (24). The SF-36 physical component was positively correlated with baseline spirometry (FVC % predicted, FEV1 % predicted, and FEV1/FVC) and diffusion capacity (see the online supplement). In addition, the SF-36 physical component was significantly reduced in persons with cough, phlegm, wheezing, and breathlessness. However, the mental component of the SF-36 correlated with neither lung function nor symptoms.
The three component scores (symptom, activity, and impact) and the total score (mean ± SE) of the SGRQ for LAM registry patients at baseline were 36.1 ± 1.50, 50.3 ± 1.98, 23.6 ± 1.22, and 34.0 ± 1.37, respectively (see Figure E2). These scores are worse than those for normal subjects with no history of respiratory disease (12, 9, 2, and 6, respectively) but better than for patients with chronic obstructive pulmonary disease (COPD; 68, 64, 46, and 52, respectively) (25, 26). The SGRQ scores were inversely related to lung function, with component and total scores most strongly associated with FEV1. In addition, all four scores were significantly inversely associated with the presence of cough, phlegm, wheezing, and breathlessness.
DISCUSSION
Because of the rarity of LAM, this registry was initiated to gather reliable information on epidemiologic and clinical features of subjects with this disorder. This summary provides demographic, clinical, and pulmonary function data about the largest cohort of patients with LAM reported to date.
The patients enrolled in the LAM registry have a broader age range than that described in previous case series originating from various countries (4–8). The reason(s) for these differences are not entirely clear, but the higher profile of LAM in the media and more liberal use of CT scanning in the United States may have allowed identification of a broader sample of patients with LAM compared with those who may have come to medical attention traditionally, that is, those who are more severely affected and at a younger age. More than one-third of our patients were postmenopausal in comparison with subjects in previous reports, who were typically in their third through fifth decades of life, with the highest percentage of postmenopausal women being 13% (6). Our cohort includes women in their eighth decade of life, some of the oldest subjects with LAM reported to date.
Not surprisingly, the vast majority of patients (86%) presented with pulmonary manifestations, including spontaneous pneumothorax, other pulmonary symptoms, and pleural effusion or other chest radiographic abnormalities. The most common symptom was breathlessness. In addition, nearly one-half of all subjects also experienced wheezing, a symptom not described in previous reports. There were no significant differences in the prevalence of various respiratory symptoms when comparing those subjects with sporadic LAM to those with TSC-LAM. There was no relevant family history for patients with sporadic LAM. As expected, some of the patients with TSC-LAM had a family history of TSC.
Hospitalization is not an uncommon event for patients with LAM. These hospitalizations are most commonly required for the management of spontaneous pneumothorax. Other reasons for hospitalization include management of chylothorax and renal angiomyolipomas that are acutely bleeding, or at risk for spontaneous hemorrhage. Unlike COPD, hospitalization for acute exacerbation of the underlying obstructive disease or respiratory failure was not seen. In the management of pleural complications nearly one-half of the patients had already undergone some form of pleurodesis. In comparing the subjects with sporadic LAM and TSC-LAM, there was no significant difference in the prevalence of previous pleurodesis. However, those with TSC-LAM were much more likely to have had a nephrectomy. This result is not surprising because these subjects are more likely to have renal angiomyolipomas and to suffer a more aggressive course with respect to the number and size of these tumors when compared with those subjects with sporadic LAM (27–29).
Airway obstruction demonstrated by spirometry was the most common pulmonary function abnormality, and was seen in more than one-half of patients. Approximately one-fourth of those subjects with obstructive defects (17% of all subjects) showed a significant increase in FEV1 after bronchodilator inhalation, similar to previous reports (7, 30). A reduced single-breath diffusing capacity was seen as commonly as airflow limitation. Given the frequency of diminished diffusing capacity in this population, exercise oximetry should be considered to exclude desaturation, and to evaluate for need of supplemental oxygen therapy. It is not clear to what extent a history of tobacco smoking might play a role in the reduction of diffusing capacity in these patients, but a smoking history would be a reasonable criterion for including the measurement of diffusing capacity in pulmonary function testing. Taveira-DaSilva and colleagues (30) detected, by cardiopulmonary exercise testing, exercise-induced hypoxemia even in patients with near-normal diffusing capacity and FEV1.
Overall, these pulmonary function results are better compared with those of previous reports (5, 7, 30). For example, Kitaichi and colleagues (5) found normal spirometric values and normal diffusing capacity in only 19 and 3% of their subjects, respectively. However, Urban and colleagues (6) described normal results on initial spirometry in 42% of their 66 patients with sporadic LAM, although in some of these patients pulmonary function results had been obtained before the diagnosis of LAM. The milder degree of pulmonary dysfunction seen in these LAM registry subjects likely reflects earlier diagnosis and detection of subclinical disease. This is due, in part, to the aggressive recruitment strategy employed by the registry to identify all subjects, rather than just those with clinically significant respiratory symptoms, and is supported by the number of subjects with normal pulmonary physiology. The early and widespread use of CT scanning to explore chest radiographic changes, or even the finding of cystic change in the lung based on abdominal CT, has likely led to the identification of cystic lung disease characteristic, or highly suggestive of, LAM in patients who are minimally symptomatic or without respiratory symptoms altogether. This is particularly true for members of the TSC-LAM subgroup, for whom the diagnosis of LAM is often made by screening chest CT of this high-prevalence subgroup (11–13). It is likely that the older age of our cohort, compared with previous reports, is also a reflection of the identification of less clinically significant disease. The TSC-LAM subgroup had a higher FEV1 and diffusing capacity as well as a slightly lower alveolar–arterial oxygen gradient reflecting milder lung involvement compared with those with sporadic LAM. Taken together, these data suggest that normal spirometry should not exclude LAM from the differential diagnosis in a young woman presenting with pneumothorax.
Estrogen has been implicated in the pathogenesis of LAM on the basis of the observation that nearly all subjects with LAM, with or without underlying TSC, have been women (1–3). In addition, exacerbation of the disease has been documented following the administration of exogenous estrogens (31, 32). Oberstein and colleagues (33) found the age of onset of symptoms to be significantly less among women using oral contraceptive pills versus nonusers and suggested that oral contraceptive pills may serve as catalysts to promote an earlier occurrence of LAM. However, hormonal receptors are inconsistently expressed in affected tissues (4, 34, 35). The LAM registry did not collect data on the dates of the last menstrual period, hormonal replacement therapy, or specific progesterone derivative used.
The therapeutic use of progestin therapy in LAM was initially described by McCarty and colleagues (36). Since this early report there have been multiple other case reports suggesting beneficial therapeutic effects of various forms of hormonal therapy for patients with LAM, but definitive evidence in this regard is lacking (1–3, 6, 37, 38). The most common medication employed in the treatment of LAM among our registry subjects was progestin therapy, which was more commonly prescribed for those with sporadic LAM compared with those with TSC-LAM. No treatment outcomes can be identified in data provided by an observational registry, such as advantage or disadvantage of progestin therapy on disease progression or complication rates. Clearly, future research must focus on targeting novel therapies to lessen the impact of this disease on this relatively young female population.
Quality-of-life data from both the SF-36 and the SGRQ confirm that patients with LAM experience impairment in quality of life. The most dramatic effect is found in the SF-36 physical component and the SGRQ activity dimension, which are, not surprisingly correlated with pulmonary function. The SF-36 physical and mental component scores for patients with LAM are worse than those for the general U.S. healthy population with no chronic conditions (55.3 and 53.4, respectively) but better than those for patients with COPD seen in one study with a mean FEV1 of 45% predicted (35.9 and 47.7, respectively) (26, 39). Interestingly, the lack of physiologic correlation with the SF-36 mental component, which is similar to patients with COPD (38, 40), suggests both groups develop coping mechanisms or have good support systems.
The relatively young age of patients affected by this disease understandably portends a greater impact on quality of life. Whereas all three SGRQ dimensions of symptom, activity, and impact were lower in this LAM cohort than for the COPD population, the effect on activity was closest to that of patients with COPD. Symptoms of LAM may be more episodic in nature (pneumothoraces, pleural effusions, and hemoptysis) as compared with the chronic breathlessness in COPD, which is reflected in the higher activity limitation scores for patients with LAM and comparatively lower symptom scores. The symptom of breathlessness may also be more acute when it occurs accompanying an event such as pneumothorax. In particular, the aversion to air travel is quite specific to this population and clearly affects activities related to quality of life. However, the occurrence of pneumothorax related to air travel was less than 5%. Patients with severely limited cardiopulmonary reserve or acute symptoms of shortness of breath should not enplane, but recommendations regarding air travel for patients with stable LAM will require directed studies. Fortunately, although pneumothorax or pleural effusion may limit planned activities, a history of their occurrence does not predict worse quality of life subsequently. In contrast, we show that previous pleurodesis does mildly affect quality of life (see the online supplement), but the degree of reduction appears not to outweigh the potential benefits of the procedure.
By its nature, the LAM registry is an observational study in which a cohort of individuals satisfying specific diagnostic criteria is monitored serially over the duration of the study. The limitations of this study include retrospective design, ascertainment by screening for some patients with TSC-LAM, requirement for sufficient reserves to travel to a specialized center for evaluation, and self-reporting of some data from memory. In addition, the predominance among the white population and the high level of education of this cohort suggest that access to health care plays a role in the identification of patients with LAM.
The strengths of this study include its size and the comprehensive nature of the patient evaluation. The results indicate that LAM usually presents with either pneumothorax or dyspnea, although in almost 25% of patients the diagnosis was made before symptoms developed. Pulmonary function testing revealed that airflow limitation is the most common presentation, but that normal spirometry is frequently seen. Gas trapping in noncommunicating airspaces is prevalent, but hyperinflation is infrequent. The diffusing capacity of carbon monoxide is reduced in most patients, and may be one of the earliest markers of the disease, based on prior studies (6, 29). Quality of life in the activity dimension for all patients is clearly impacted by breathlessness, multiple hospitalizations for acute events related to LAM complications, and limitations to air travel. This report provides descriptive data related to diagnostic hallmarks that could contribute to earlier identification of LAM, for example, pneumothorax being the most common presenting symptom in a comparatively young female population. Future reports from the LAM registry will describe lung transplantation in patients with LAM, the reliability of CT criteria for diagnosis of LAM as compared with tissue diagnosis, and longitudinal data from this cohort, which will help define the natural history of the disease and form a foundation for future clinical trials.
NHLBI LAM Registry Group: NHLBI Project Office—H. H. Peavy, J. P. Kiley, M. Stylianou, C. D. Vreim, M. C. Wu; National Heart, Lung, and Blood Institute— J. Moss, A. Taveira-DaSilva, P. M. Barnes, M. B. Barton, M. E. Ehrmantraut, C. G. Glasgow, C. J. Jolley, E. Lange, R. A. Litzenberger, P. J. McGraw, W. K. Steagall; Steering Committee Chair—J. H. Ryu (B. L. Fanburg, previous); Cleveland Clinic Foundation—J. T. Chapman, J. R. Maurer, E. J. Sullivan, A. C. Arroliga, H. A. Christie, S. M. Lubell, Y. Meli; Mayo Clinic—E. J. Olson, S. D. Fisher, J. H. Ryu; National Jewish Medical and Research Center—K. K. Brown, D. Kervitsky, M. E. Wallace; New England Medical Center—G. A. Finlay, B. L. Fanburg, R. Tsacoyianis; Stanford University Medical Center—S. J. Ruoss, S. S. Jacobs, T. A. Raffin; Data Coordinating Center (Cleveland Clinic Foundation)—G. J. Beck, J. C. Lee, X. Liu, J. McMahan, S. G. Sherer, J. K. Stoller, L. J. Tuason; Imaging Core—M. Meziane, D. A. Lynch, P. B. O'Donovan; Pulmonary Function Core—K. McCarthy; Tissue Core— K. K. Brown, J. Moss, V. J. Ferrans, F. Giacometti, W. D. Travis; Tissue Repository (BBI-BioTech Research Laboratories)—M. Cosentino, C. Chorley, M. Dowell, Kathi Shea; Consultants—S. Byrnes, E. P. Henske, T. E. King, Jr., F. X. McCormack, J. D. Moreno; Data and Safety Monitoring Board—G. Hunninghake, A. S. Buist, K. M. Detre, M. L. Foegh, C. Ober.
Acknowledgments
The authors thank the patients with LAM, who gave generously of their time for this study; and the referring physicians, the LAM Foundation, and the Tuberous Sclerosis Alliance for help with recruitment of patients.
FOOTNOTES
Supported by NHLBI grant U01 HL58440 and the NHLBI Division of Intramural Research.
This article has an online supplement, which is accessible from this issue's table of contents at www.atsjournals.org
Originally Published in Press as DOI: 10.1164/rccm.200409-1298OC on October 6, 2005
Conflict of Interest Statement: J.H.R. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. J.M. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. G.J.B. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. J.-C.L. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. K.K.B. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. J.T.C. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. G.A.F. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. E.J.O. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. S.J.R. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. J.R.M. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. T.A.R. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. H.H.P. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. K.M. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. A.T.-D. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. F.X.M. is the scientific director of the Lymphangioleiomyomatosis (LAM) Foundation. N.A.A. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. R.M.D. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. S.S.J. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. M.S. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. B.L.F. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript.
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