Effect of mTOR inhibitors on the mortality and safety of patients with lymphangioleiomyomatosis on the lung transplantation waitlist: A retrospective cohort study.

BACKGROUND: Although lung transplantation (LTx) is the last resort for patients with end-stage lymphangioleiomyomatosis (LAM), the high waitlist mortality is a source of concern in Japan. Discontinuation of mechanistic target of rapamycin (mTOR) inhibitors prior to LTx is recommended due to the incidence of severe adverse events. Therefore, we hypothesized that mTOR inhibitors may affect the mortality of patients with LAM on the LTx waitlist. METHODS: We retrospectively compared the characteristics of consecutive patients with LAM on the LTx waitlist who were and were not receiving mTOR inhibitors. RESULTS: Twenty-nine consecutive patients with LAM who listed our center between January 2004 and December 2021 were selected from the database and enrolled in the present study. Seventeen patients (58.6%) were receiving a mTOR inhibitor, sirolimus (treatment group). During a median listing period of 1277 days, 12 patients (41.4%) were hospitalized, six patients (20.7%) died from disease before LTx, and 15 patients underwent LTx. Among the deceased patients, four patients (66.6%) had pneumothoraces. The waitlist mortality in the treatment group was significantly lower than that in the non-treatment group (p = 0.03). Among the six patients who discontinued sirolimus in the treatment group, four patients (66.6%) were hospitalized with respiratory complications after the discontinuation of sirolimus. No mTOR inhibitor-related complications arose in the treatment group undergoing LTx (n = 7), including those on a reduced sirolimus dose. CONCLUSIONS: Administration of an mTOR inhibitor until LTx may decrease waitlist mortality. Due to life-threatening events after discontinuing sirolimus pre-LTx, a reduced dose until LTx is permissible.

Linfangioleiomiomatosis pulmonar / Pulmonary lymphangioleiomyomatosis

Introducción: La linfangioleiomiomatosis pulmonar constituye un desafío, tanto en su manejo diagnóstico como en la atención de sus complicaciones. Es una enfermedad rara que se caracteriza por la proliferación del músculo liso alrededor de las estructuras bronco-vasculares, linfáticos y en el intersticio pulmonar, unido a la dilatación quística de los espacios aéreos terminales. Objetivo: Describir la evolución clínica y el tratamiento de un paciente con linfangioleiomiomatosis pulmonar. Presentación de caso: Se presenta un caso de linfangioleiomiomatosis pulmonar que desde el punto de vista clínico se manifestó por neumotórax a repetición. Se llegó a diagnóstico definitivo mediante la realización de una biopsia de pulmón. Desarrollo: La linfangioleiomiomatosis es una entidad rara que afecta fundamentalmente a mujeres en edad fértil y que se caracteriza por la presencia de un patrón quístico difuso. Su prevalencia e incidencia es desconocida. Conclusiones: Se puede concluir que la presencia de neumotórax espontáneo o recidivante en una mujer en edad fértil, o embarazada, debe sospecharse linfangioleiomiomatosis(AU)

Introduction: Pulmonary lymphangioleiomyomatosis constitutes a challenge, both in its diagnostic management and in the care of complications. It is a rare disease characterized by the proliferation of smooth muscle around the bronchovascular and lymphatic structures and in the pulmonary interstitium, together with cystic dilation of the terminal air spaces. Objective: To describe a diagnosed case of pulmonary lymphangioleiomyomatosis. Case report: A case of pulmonary lymphangioleiomyomatosis is reported, which was clinically showed as recurrent pneumothorax. A definitive diagnosis was reached by performing a lung biopsy. Discussion: Lymphangioleiomyomatosis is a rare entity that mainly affects women of childbearing age and is characterized by the presence of a diffuse cystic pattern. Its prevalence and incidence is unknown. Conclusions: It can be concluded that the presence of spontaneous or recurrent pneumothorax in a woman of childbearing age, or pregnant, should be suspected lymphangioleiomyomatosis(AU)

Lymphangioleiomyomatosis.

BACKGROUND: Lymphangioleiomyomatosis (LAM) is a rare systemic disease that occurs sporadically (S/LAM) or as part of tuberous sclerosis (TS/LAM). LAM is characterized by proliferation of abnormal smooth muscle cells. This disease clinically manifests as dyspnea on exertion and pneumothorax. Lymphadenopathy in the abdominal and pelvic region leading to lymphatic obstruction can also occur. LAM is associated with kidney angiomyolipoma and meningioma. The disease is diagnosed histologically and/or using typical high-resolution computed tomography findings and anamnestic information. In histopathological studies, the diagnosis is supported by detection of characteristic LAM cells. Mammalian target of rapamycin (mTOR) inhibitors are possible treatment options. MATERIAL AND METHODS: Ten consecutive patients diagnosed with LAM and pulmonary manifestation (eight with S/LAM and two with TS/LAM) in 2002-2018 were retrospectively analyzed. Their individual clinical characteristics and our treatment experience are described. RESULTS: The patients varied in terms of disease stage. The best predictors of prognosis were lung function parameters (forced vital capacity, forced expiratory volume in 1 second, and diffusing capacity for carbon monoxide). Four patients are currently being treated with mTOR inhibitors. This treatment stabilized lung functions in all four patients. The median follow-up was 48 months (12-132 months). Median survival was not achieved and only three patients died. CONCLUSION: An interdisciplinary approach is required to care for LAM patients. Cooperation of pneumologists, surgeons, oncologists, and geneticists is needed. Treatment with mTOR inhibitors led to stabilization in our patients. The side effects were well managed.

Clinical outcomes and survival following lung transplantation in patients with lymphangioleiomyomatosis.

BACKGROUND: The primary aim of our study was to derive disease-specific outcomes following lung transplantation (LT) in patients with lymphangioleiomyomatosis (LAM). METHODS: We queried the Organ Procurement and Transplant Network database to identify LAM patients that have undergone LT in the United States. The overall survival was analyzed with Kaplan-Meier curves. Survival estimates between subgroups of interest were compared using the log-rank method. Cox proportional hazard models were employed to determine the pre-transplant variables that impact post-LT survival. RESULTS: One hundred and thirty-eight women with LAM underwent LT at 31 centers between January 2003 and June 2017. The median age at listing and transplant was 44 (IQR: 36-51) and 45 (IQR: 38-52) years, respectively. The median time spent on the LT waitlist was 257 (IQR: 85-616) days. The majority of the patients (109/134, 81%) received bilateral sequential LT. The median ischemic time was 4.9 (IQR: 4.1-6.1) hours. The actuarial Kaplan-Meier survival following LT for LAM patients at 1-, 5-, and 10 years was 94%, 73% and 56%, respectively. The post-LT survival was significantly better in LAM than in other lung diseases (10-year survival 56% vs. 32%, p < 0.01), and this advantage persisted after age- and gender-matched analysis (10-year survival 54% vs. 37%, p < 0.01). Pre-transplant parameters, such as the presence of pulmonary hypertension, six-minute walk distance, age at transplant, ischemic time during transplant, or type of transplant (single vs bilateral sequential LT), did not affect post-transplant survival. CONCLUSIONS: The median survival after LT in LAM is 12 years and is substantially better than in other lung diseases.

Long-Term Results of Bilateral Lung Transplantation in Patients With End-Stage Pulmonary Lymphangioleiomyomatosis.

INTRODUCTION: Lymphangioleiomyomatosis (LAM) is a rare disease in women, leading to progressive deterioration of lung function and respiratory failure. We describe the outcome of patients with end-stage LAM who underwent lung transplantation at our center. MATERIALS AND METHODS: The records of patients with LAM transplanted at our institution between February 1997 and May 2015 were reviewed retrospectively. Morbidity and mortality were analyzed, and actuarial survival was calculated using Kaplan-Meier methods. The cumulative survival of transplant patients with LAM at our center was compared with survival after transplantation due to different diseases at our center and the results of the International Society for Heart and Lung Transplantation. Quality of life was assessed by a patient self-report at the end of the first postoperative year. RESULTS: During the study period, 25 patients underwent lung transplantation for LAM. All patients were women with a mean age of 50 (9) years. Thirteen patients (52%) had undergone previous thoracotomy. All patients (100%) received bilateral lung transplantation. One (4%) case of in-hospital mortality occurred and 9 (36%) late deaths. Two (8%) cases of late death were due to chronic lung allograft dysfunction. The 1-, 3-, and 5-year survival rates were 92%, 84%, and 76%, respectively. Quality-of-life ratings were above the normal in all eight 36-Item Short Form Health Survey subscales 1 year after transplantation. CONCLUSIONS: Lung transplantation offers a valuable therapy for patients with end-stage pulmonary LAM.

The NHLBI LAM Registry: Prognostic Physiologic and Radiologic Biomarkers Emerge From a 15-Year Prospective Longitudinal Analysis.

BACKGROUND: The natural history of lymphangioleiomyomatosis (LAM) is mainly derived from retrospective cohort analyses, and it remains incompletely understood. A National Institutes of Health LAM Registry was established to define the natural history and identify prognostic biomarkers that can help guide management and decision-making in patients with LAM. METHODS: A linear mixed effects model was used to compute the rate of decline of FEV1 and to identify variables affecting FEV1 decline among 217 registry patients who enrolled from 1998 to 2001. Prognostic variables associated with progression to death/lung transplantation were identified by using a Cox proportional hazards model. RESULTS: Mean annual decline of FEV1 was 89 ± 53 mL/year and remained remarkably constant regardless of baseline lung function. FEV1 decline was more rapid in those with greater cyst profusion on CT scanning (P = .02) and in premenopausal subjects (118 mL/year) compared with postmenopausal subjects (74 mL/year) (P = .003). There were 26 deaths and 43 lung transplantations during the evaluation period. The estimated 5-, 10-, 15-, and 20-year transplant-free survival rates were 94%, 85%, 75%, and 64%, respectively. Postmenopausal status (hazard ratio, 0.30; P = .0002) and higher baseline FEV1 (hazard ratio, 0.97; P = .008) or diffusion capacity of lung for carbon monoxide (hazard ratio, 0.97; P = .001) were independently associated with a lower risk of progression to death or lung transplantation. CONCLUSIONS: The median transplant-free survival in patients with LAM is > 20 years. Menopausal status, as well as structural and physiologic markers of disease severity, significantly affect the rate of decline of FEV1 and progression to death or lung transplantation in LAM.

The vitamin D binding protein axis modifies disease severity in lymphangioleiomyomatosis.

Lymphangioleiomyomatosis (LAM) is a rare disease of women. Decline in lung function is variable, making appropriate targeting of therapy difficult. We used unbiased serum proteomics to identify markers associated with outcome in LAM.101 women with LAM and 22 healthy controls were recruited from the National Centre for LAM in the UK. 152 DNA and serum samples with linked lung function and outcome data were obtained from patients in the National Heart, Lung and Blood Institute LAM Registry in the USA. Proteomic analysis was performed on a discovery cohort of 50 LAM and 20 control serum samples using a SCIEX SWATH mass spectrometric workflow. Protein levels were quantitated by ELISA and single nucleotide polymorphisms in GC (group-specific component) encoding vitamin D binding protein (VTDB) were genotyped.Proteomic analysis showed VTDB was 2.6-fold lower in LAM than controls. Serum VTDB was lower in progressive compared with stable LAM (p=0.001) and correlated with diffusing capacity of the lung for carbon monoxide (p=0.01). Median time to death or lung transplant was reduced by 46 months in those with CC genotypes at rs4588 and 38 months in those with non-A-containing haplotypes at rs7041/4588 (p=0.014 and 0.008, respectively).The VTDB axis is associated with disease severity and outcome, and GC genotype could help predict transplant-free survival in LAM.

Single lung transplantation for lymphangioleiomyomatosis: a single-center experience in Japan.

PURPOSE: Lung transplantation is accepted as an effective modality for patients with end-stage pulmonary lymphangioleiomyomatosis (LAM). Generally, bilateral lung transplantation is preferred to single lung transplantation (SLT) for LAM because of native lung-related complications, such as pneumothorax and chylothorax. It remains controversial whether SLT is a suitable surgical option for LAM. The objective of this study was to evaluate the morbidity, mortality and outcome after SLT for LAM in a lung transplant center in Japan. METHODS: We reviewed the records of 29 patients who underwent SLT for LAM in our hospital between March, 2000 and November, 2017. The data collected included the pre-transplant demographics of recipients, surgical characteristics, complications, morbidity, mortality and survival after SLT for LAM. RESULTS: The most common complication after SLT for LAM was contralateral pneumothorax (n = 7; 24.1%). Six of these recipients were treated successfully with chest-tube placement and none required surgery for the pneumothorax. The second-most common complication was chylous pleural effusion (n = 6; 20.7%) and these recipients were all successfully treated by pleurodesis. The 5-year survival rate after SLT for LAM was 79.5%. CONCLUSION: LAM-related complications after SLT for this disease can be managed. SLT is a treatment option and may improve access to lung transplantation for patients with end-stage LAM.

Lymphangioleiomyomatosis and Tuberous Sclerosis Complex in Quebec: Prevalence and Health-care Utilization.

BACKGROUND: Lymphangioleiomyomatosis (LAM) is a manifestation of tuberous sclerosis complex (TSC) that causes destruction of the lung and chronic respiratory failure. Population-based estimates of demographics, clinical outcomes, and health-care utilization are lacking for TSC and LAM. METHODS: Data on demographics, clinical outcomes, and health-care utilization in the Quebec ministerial provincial health-care database were analyzed for their association with TSC and LAM. RESULTS: A total of 1,004 subjects with TSC were identified using International Classification of Diseases, Ninth and 10th Revisions, codes for a prevalence of one in 7,872 people. There were 38 subjects with LAM, nine of whom also had TSC. Mean ages as well as the mean age at death were lower in the LAM and TSC group than in the control group. Mortality rates were higher in subjects with LAM than in those with TSC or in control subjects. Subjects with LAM experienced more medical visits and hospitalizations than did those with TSC and control subjects; these were associated with higher health-care costs. Frequently prescribed drugs in TSC or LAM included anticonvulsants, antidepressants, and sedatives; the use of mammalian target of rapamycin inhibitors was uncommon. CONCLUSIONS: The prevalence of TSC in Quebec, Canada, is similar to estimates from previously published surveys. LAM is likely underreported, perhaps due to suboptimal case identification or referral. Health-care utilization and mortality for LAM are high, suggesting that timely diagnosis and therapy could be beneficial. Mental health disorders may be an unrecognized clinical feature of LAM. These results provide a population-based background for policymakers and researchers to better address the needs of patients with TSC and LAM.

Clinical course and characterisation of lymphangioleiomyomatosis in a Brazilian reference centre.

BACKGROUND AND OBJECTIVE: Lymphangioleiomyomatosis (LAM) is a rare disease that promotes pulmonary cystic destruction and impairs pulmonary function. We aim to describe features and clinical course of LAM patients from Brazil. METHODS: We described the clinical and functional features, performance in six minute walk test (6MWT), management details, survival and clinical course of 84 LAM patients followed in a Brazilian reference centre. RESULTS: All subjects were women, the average age at onset of symptoms was 38 years, and the average at diagnosis was 42 years. The major symptoms during the course of the disease were dyspnoea and pneumothorax. The patients experienced impaired quality of life, with worse scores in the physical and emotional domains. The most common abnormalities in pulmonary function tests were an obstructive pattern and reduced diffusion capacity, whereas a quarter of the patients had normal spirometric results. In the 6MWT, although patients had preserved exercise capacity, more than half of the patients had significant desaturation. Hormonal blockage and doxycycline were the most common treatment modalities employed in our patients. The survival probability from diagnosis was 90% at 5 years, whereas the mean annual rate of decline in FEV1 was 60 ± 78 mL. CONCLUSIONS: Clinical and functional features of the LAM patients from our centre are similar to those from other countries. Our sample showed preserved exercise capacity, with desaturation in the 6MWT, and impaired quality of life. Survival was similar, whereas the annual rate of decline of FEV1 was slightly lower than in recent studies.

[Lung transplantation in sporadic lymphangioleiomyomatosis: study of 7 cases]. / Trasplante pulmonar en la linfangioleiomiomatosis esporádica. Estudio de 7 casos.

BACKGROUND AND OBJECTIVE: Sporadic lymphangioleiomyomatosis (S-LAM) is a rare disease that affects only women. It is characterized by an abnormal proliferation of immature smooth muscle cells (LAM cells) that grow in an aberrant manner in the airway, parenchymal lung lymph and blood vessels, determining the onset of pulmonary cystic lesions. The disease has no treatment, progressing to respiratory failure, and lung transplantation (LT) may be a treatment option at this stage. Our goal was to study 7 patients undergoing LT for S-LAM. MATERIAL AND METHOD: We studied a series of clinical and demographic characteristics, diagnostic modality and post-transplant outcomes. We performed a descriptive analysis of the series. The Kaplan-Meier method was used to estimate survival. RESULTS: The mean age of onset of symptoms was 35 years, the diagnosis of 37 years and that of LT 38 years. The most common symptom was dyspnea. Four patients had a history of pneumothorax and pleural effusion. The mean forced expiratory volume in one second was 32.7% and the diffusing capacity for carbon monoxide was 29%. All patients were subjected to LT and survival was 100, 85.7 and 57.1% at one, 3 and 5 years, respectively. Three died of bronchiolitis obliterans and 2 necropsies did not show evidence of disease recurrence. CONCLUSIONS: LT is a therapeutic option in patients with S-LAM with an advanced respiratory functional impairment.

[Perioperative management of lung transplantations in patients with pulmonary arterial hypertension compared with that in patients with lymphangiomyomatosis].

BACKGROUND: The number of lung transplantation has tended to increase as a treatment for patients with pulmonary arterial hypertension (PAH) and lymphangiomyomatosis (LAM) in Japan. However, we have little evidence about the comparison of perioperative management in patients with PAH and that in patients with LAM. METHODS: In this retrospective study, ten patients with PAH and seventeen patients with LAM who underwent the lung transplantations between 2006 and 2011 were enrolled. RESULTS: PAH patients received double lung transplantation with intraoperative cardiopulmonary bypass (CPB) support. Before anesthesia induction, percutaneous cardiopulmonary support (PCPS) was begun. Most of LAM patients received single lung transplantation without using CPB support and PCPS support before anesthesia induction. But sometimes during an operation PCPS support was necessary. Postoperative PCPS support showed no significant differences between PAH and LAM. The four year survival rate was 80% (PAH) and 87.8% (LAM). Pao2/FIo2 in patients with PAH and in those with LAM, %FEV10 in those with LAM after surgery improved when compared to those before surgery. CONCLUSIONS: The large difference in perioperative management between patients with PAH and those with LAM is an important knowledge for anesthesist.

Clinical predictors of mortality and cause of death in lymphangioleiomyomatosis: a population-based registry.

PURPOSE: Lymphangioleiomyomatosis (LAM) is a rare, progressive, frequently lethal cystic lung disease that almost exclusively affects women. Prognostic information in LAM has been limited by small numbers and heterogeneous study methodology. Early retrospective cohorts cited 5- and 10-year mortality of 40 and 80 %, respectively. More recently, mortality at 10 years has been estimated to be approximately 10-20 % from the onset of symptoms and 30 % at 10 years from the time of lung biopsy but varies widely in individual patients. Given the heterogeneous disease course, it would be useful to establish which clinical characteristics are associated with survival to develop prediction models for disease outcome. METHODS: The LAM Foundation maintains a population-based registry of 1,149 registered self-identified LAM patients. Of these, 590 have completed a "General Information/Clinical History Questionnaire" with limited demographic and clinical data, 410 of whom were identified as U.S. residents and provided date of birth. Vital status was obtained on all 410 participants through December 31, 2007 by linking patient identifiers and the National Death Index. Survival time was calculated as the time since first lung-related symptom or physician diagnosis until censoring (still alive, received lung transplant, or died). Cox proportional hazard analysis evaluated the association of demographic and clinical features with survival. RESULTS: Among the 410 subjects, there were 50 deaths and 55 lung transplantations during a median of 10.4 years of observation time. The estimated median transplant-free survival time for LAM patients in the United States is 29 years from symptom onset and 23 years from diagnosis. The estimated 10-year survival transplant-free was 86 %. Age at disease onset, smoking status, race, presence of tuberous sclerosis, occurrence of pneumothorax, and pregnancy did not demonstrate an association with survival or transplant. Greater age at presentation and presence of angiomyolipoma were associated with less risk of mortality. Treatment with hormonal therapy was associated with an increased risk of death/transplant (hazard ratio (HR) 2.93; 95 % confidence interval (CI), 1.54-5.58; p = 0.001), particularly progesterone therapy (HR 2.17; 95 % CI 1.26-3.75, p = 0.005), and may represent confounding by indication. Patients who required oxygen therapy had a worse outcome (HR 4.53; 95 % CI 2.76-7.42; p < 0.001). CONCLUSIONS: Our population-based study showed that the median survival in patients with LAM from the onset of symptoms or diagnosis is much longer than previously described. This has important implications for life choices and treatment decisions regarding medication use and lung transplantation for patients with LAM.

Lymphangioleiomyomatosis--a brief review and estimation of excess risk.

Lymphangioleiomyomatosis (LAM) is a rare pulmonary disease in women of child-bearing age. It is multisystem disease and affects mainly the lungs. A recently published Korean medical article showed a sharp increase of LAM patients in Korea since 2004. LAM is not discussed in the standard textbook of insurance medicine. This article will briefly review LAM and estimate excess risk derived from recently published articles.

Pulmonary hypertension in lymphangioleiomyomatosis: characteristics in 20 patients.

This retrospective, multicentre study evaluated patients with lymphangioleiomyomatosis (LAM) and pre-capillary pulmonary hypertension (PH) by right heart catheterisation. It was conducted in 20 females with a mean ± SD age of 49 ± 12 yrs and a mean ± SD time interval between LAM and PH diagnoses of 9.2 ± 9.8 yrs. All, except for one patient, were receiving supplemental oxygen. 6-min walking distance was mean ± SD 340 ± 84 m. Haemodynamic characteristics were: mean pulmonary artery pressure (PAP) 32 ± 6 mmHg, cardiac index 3.5 ± 1.1 L · min(-1) · m(-2) and pulmonary vascular resistance (PVR) 376 ± 184 dyn · s · cm(-5). Mean PAP was >35 mmHg in only 20% of cases. The forced expiratory volume in 1 s was 42 ± 25%, carbon monoxide transfer factor was 29 ± 13%, and arterial oxygen tension (P(a,O(2))) was 7.4 ± 1.3 kPa in room air. Mean PAP and PVR did not correlate with P(a,O(2)). In six patients who received oral pulmonary arterial hypertension (PAH) therapy, the PAP decreased from 33 ± 9 mmHg to 24 ± 10 mmHg and the PVR decreased from 481 ± 188 dyn · s · cm(-5) to 280 ± 79 dyn · s · cm(-5). The overall probability of survival was 94% at 2 yrs. Pre-capillary PH of mild haemodynamic severity may occur in patients with LAM, even with mild pulmonary function impairment. PAH therapy might improve the haemodynamics in PH associated with LAM.

A nationwide survey of lymphangioleiomyomatosis in Korea: recent increase in newly diagnosed patients.

In 2007, the Korean Interstitial Lung Disease Society had collected clinical data of patients who have diagnosed as Lymphangioleiomyomatosis (LAM) since 1990 through nationwide survey, which showed that LAM patients had increased sharply after 2004. The present study was performed to show the clinical features of Korean patients with LAM, and to establish the reason for the recent increase in the diagnosis. All 63 patients were women and the mean age at diagnosis was 36 yr. The most common presenting symptom was dyspnea and 8 patients had tuberous sclerosis complex. The survival rate at 5 yr after diagnosis was 84%. Compared with patients diagnosed after 2004 (n=34), the patients diagnosed before 2004 (n=29) complained with dyspnea more (P=0.016) and had lower FEV(1)% predicted (P=0.003), and DLco% predicted (P=0.042). The higher proportion of patients diagnosed after 2004 showed the normal chest radiography, and they were detected by routine chest CT screening (P=0.016). This study showed that clinical features of Korean patients with LAM were not different from those reported elsewhere. It is concluded that the reason for the increase of newly diagnosed patients is the result of increase in detection of the early stage LAM by the widespread use of chest CT screening.

The epidemiology of lymphangioleiomyomatosis in Japan: a nationwide cross-sectional study of presenting features and prognostic factors.

BACKGROUND AND OBJECTIVE: To evaluate the characteristics and prognostic factors of Japanese patients with lymphangioleiomyomatosis (LAM). METHODS: A nationwide survey to identify patients with LAM was conducted by questionnaire. Survival probability was estimated using the Kaplan-Meier method, and the prognostic factors were analysed by Cox regression. RESULTS: Data were collected on 173 patients with pulmonary LAM. The major presenting features were pneumothorax (43%) and exertional dyspnoea (37%). The survival probabilities for patients presenting with exertional dyspnoea (Group A) were 85%, 60% and 47% after 5, 10 and 15 years, respectively, and for patients presenting with pneumothorax (Group B) were 95%, 89% and 89%, respectively. Although the age at symptom onset was higher among patients in Group A than in Group B, Cox regression revealed that the presenting feature was a prognostic factor independent of age at symptom onset (Group A/B hazard ratio = 5.732, P < 0.01). In the subgroup of patients whose initial FEV(1) was >1000 mL, or FEV(1)/FVC >40%, or %DL(CO) >40%, the rate of deterioration in these tests was greater in Group A than in Group B (P < 0.01 for FEV(1), P < 0.05 for FEV(1)/FVC and %DL(CO)). CONCLUSIONS: There are two possible subgroups of LAM patients. One subgroup that presented with pneumothorax, had onset of symptoms at a younger age and a more favourable prognosis; the other presented with exertional dyspnoea, had onset of symptoms at an older age and a poorer prognosis.