Epidemiology of patients with lymphangioleiomyomatosis: A descriptive study using the national database of health insurance claims and specific health checkups of Japan.

BACKGROUND: Using patient registries or limited regional hospitalization data may result in underestimation of the incidence and prevalence of rare diseases. Therefore, we used the national administrative database to estimate the incidence and prevalence of lymphangioleiomyomatosis over six years (2014-2019) and describe changes in clinical practice and mortality. METHODS: We extracted data from the National Database of Health Insurance Claims and Specific Health Checkups of Japan between January 2013 and December 2020. This database covers ≥99% of the population. We used the diagnostic code for lymphangioleiomyomatosis to estimate the incidence and prevalence from 2014 to 2019. Additionally, we examined the demographic characteristics, treatments, comorbidities, and mortality of the patients. RESULTS: In women, the incidence and prevalence of lymphangioleiomyomatosis in 2019 were approximately 3 per 1,000,000 person-years and 28.7 per 1,000,000 persons, respectively. While, in men, the incidence and prevalence of lymphangioleiomyomatosis were <0.2 per 1,000,000 person-years and 0.8 per 1,000,000 persons, respectively. From 2014 to 2019, the proportion of prescriptions of sirolimus and everolimus increased, while the use of home oxygen therapy, chest drainage, comorbid pneumothorax, and bloody phlegm decreased. The mortality rate remained stable at approximately 1%. CONCLUSIONS: The incidence and prevalence of lymphangioleiomyomatosis were higher in women than those reported previously. Although the incidence did not change during the 6-year period, the prevalence gradually increased. Moreover, lymphangioleiomyomatosis was observed to be rare in men. The practice of treating patients with lymphangioleiomyomatosis changed across the six years while mortality remained low, at approximately 1%.

Intraoperative mechanical ventilation and incidence of pneumothorax in lymphangioleiomyomatosis.

Patients with lymphangioleiomyomatosis (LAM) are considered high risk for most surgeries and require specific anesthetic considerations mainly because of the common spontaneous pneumothorax (PTX). To explore whether intraoperative mechanical ventilation could increase the risk of PTX in those patients, we included 12 surgical patients with LAM in this study, of whom four (33.3%) experienced postoperative PTX. According to our results, patients with higher CT grade, poorer pulmonary function, and a history of preoperative PTX might be more likely to develop postoperative PTX. However, intraoperative mechanical ventilation did not show obvious influence, which might help clinicians reconsider the perioperative management of LAM patients.

Sirolimus reduces the risk of pneumothorax recurrence in patients with lymphangioleiomyomatosis: a historical prospective self-controlled study.

BACKGROUND: Spontaneous pneumothorax has a high incidence and high rate of recurrence in patients with lymphangioleiomyomatosis (LAM). The risk factors for pneumothorax and the effects of sirolimus on pneumothorax in patients with LAM are unknown. In our study, multivariate logistic regression was applied to a cross-sectional cohort to investigate factors associated with pneumothorax in LAM patients. Kaplan-Meier analysis was applied in the historical prospective self-controlled study to determine whether sirolimus reduces the risk of pneumothorax recurrence in patients with LAM. RESULTS: Of the 399 patients registered with LAM-CHINA at our center between May 10, 2017 and August 31, 2020, 142 had a history of pneumothorax at registration. High CT grade and age at presentation ≤ 35 years were associated with a higher risk of pneumothorax in patients with LAM. Postmenopausal status was correlated with a lower risk of pneumothorax. In the historical prospective self-controlled study, the 5-year probability of pneumothorax recurrence was 80% lower in the sirolimus group than in the control group (hazard ratio for pneumothorax recurrence, 0.20; 95% CI, 0.14 to 0.30, P < 0.001 by log-rank test). CONCLUSION: Sirolimus reduced the risk of pneumothorax recurrence in LAM patients.

Hierarchical cluster analysis based on disease-associated manifestations of patients with lymphangioleiomyomatosis: An analysis of the national database of designated intractable diseases of Japan.

BACKGROUND: Lymphangioleiomyomatosis (LAM) is a rare multisystem disease with variable manifestations and differing rates of progression among individuals. Classification of its phenotypes is an issue for consideration. We hypothesized that clinical manifestations associated with LAM cluster together and identifying these associations would be useful for identifying phenotypes. METHODS: Using cross-sectional data from the National Database of Designated Intractable Diseases of Japan, we performed a hierarchical cluster analysis based on disease-associated manifestations. RESULTS: Four clusters were identified from 404 patients (50.4% of 801 LAM patients registered in 2016). Patients in cluster 1 had only dyspnea on exertion, relatively low lung function, the earliest onset age, and the lowest prevalence of tuberous sclerosis complex (TSC). Those in cluster 2 had various manifestations with the highest prevalence of TSC. Patients in cluster 3 had major respiratory symptoms (cough, sputum, or dyspnea on exertion) or fatigue and the lowest lung function. Those in cluster 4 were asymptomatic and had the latest onset age, shortest disease duration, and relatively high prevalence of TSC. Patients in cluster 1 had the highest rate of receiving mechanistic target of rapamycin (mTOR) inhibitor treatment, suggesting that cluster 1 included those with declining lung function for which mTOR inhibitor treatment was required. CONCLUSIONS: Hierarchical cluster analysis based on manifestations data identified four clusters. The characteristics of cluster 1 are noteworthy in relation to the indication for mTOR inhibitor treatment. A cluster analysis of accumulated and longitudinal data that allows valid clustering and outcome comparisons is required in the future.

Lung Diseases Unique to Women.

The differences in the respiratory system between women and men begin in utero. Biologic sex plays a critical role in fetal development, airway anatomy, inhalational exposures, and inhaled particle deposition of the respiratory system, thus leading to differences in risk for disease, as well as clinical manifestations, morbidity, and mortality. In this article, we focus on those respiratory diseases unique to females: lymphangioleiomyomatosis and thoracic endometriosis syndrome.

Description of a multidisciplinary model of care in a French cohort of adult patients with tuberous sclerosis complex.

BACKGROUND: Tuberous sclerosis complex (TSC) is a rare autosomal dominant genetic disorder. Due to the various manifestations of TSC and their potential complications, a multidisciplinary care approach is recommended by consensus guidelines. OBJECTIVES: Our study aimed to give a complete description of our TSC adult cohort and to evaluate the multidisciplinary and interdisciplinary management model. METHODS: Data on each adult patient diagnosed with TSC, including disease manifestations, interventions and outcomes, were collected at baseline and updated annually. A multidisciplinary TSC approach with all the recommended explorations was carried out annually. RESULTS: 90 patients were enrolled in Centre Hospitalier Universitaire de Bordeaux, between January 2000 and September 2018. Median age of patients at inclusion was 37 years (range, 27-47) and 20 years old at diagnosis of TSC. Regarding the occurrence of TSC manifestations, 97% of the patients had cutaneous lesions, 89% had neurological manifestations, 83% had renal manifestations and 100% had dental lesions with pits. More than half the patients had sclerotic bone lesions (68%), TSC-associated neuropsychiatric disorders (64%) and lymphangioleiomyomatosis (59%). A TSC multidisciplinary approach was developed including a global follow-up and an evaluation of TSC targeting organs, according to the recommendations. A satisfaction survey revealed global and entire satisfaction of patients with TSC. CONCLUSION: We obtained an accurate description of a cohort of adult patients with TSC. Our multidisciplinary approach model allowed us to provide optimal management of patients with TSC with a high level of patient satisfaction.

Ultra-rare cystic disease.

Diffuse cystic lung diseases include a group of heterogeneous disorders characterised by the presence of cysts within the lung parenchyma, sometimes showing a characteristic computed tomography scan pattern that allows diagnosis. The pathogenetic mechanisms underlying cyst formation in the lung are still not clear and a number of hypotheses have been postulated according to the different aetiologies: ball-valve effect, ischaemic dilatation of small airways and alveoli related to infiltration and obstruction of small vessels and capillaries that supply the terminal bronchioles and connective tissue degradation by matrix metalloproteases. A wide number of lung cyst diseases have been classified into six diagnostic groups according to the aetiology: neoplastic, congenital/genetic, lymphoproliferative, infective, associated with interstitial lung diseases, and other causes. This article focuses on lymphangioleiomyomatosis, pulmonary Langerhans cell histiocytosis and Erdheim-Chester disease, Birt-Hogg-Dubé, follicular bronchiolitis and lymphocytic interstitial pneumonia, light-chain deposition disease and amyloidosis, congenital lung disease associated with aberrant lung development and growth, and cystic lung disease associated with neoplastic lesion. These cystic diseases are epidemiologically considered as ultra-rare conditions as they affect fewer than one individual per 50 000 or fewer than 20 individuals per million. Despite the rarity of this group of disorders, the increasing use of high-resolution computed tomography has improved the diagnostic yield, even in asymptomatic patients allowing prompt and correct therapy and management without the need for a biopsy.

Tuberous sclerosis complex (TSC), lymphangioleiomyomatosis, and COVID-19: The experience of a TSC clinic in Italy.

Individuals with comorbidities are at higher risk of coronavirus disease 2019 (COVID-19) and worse outcome, but little information has been available about patients with genetic diseases and COVID-19. This study aims at evaluating the presence and outcome of COVID-19 in a cohort of Italian patients with tuberous sclerosis complex (TSC) and/or lymphangioleiomyomatosis (LAM), and at reviewing the possible effects of mTOR inhibitors on SARS-CoV-2 infection. We included 102 unselected individuals with a diagnosis of TSC and/or LAM assessed between January 1, 2020 and April 24, 2020 (29% children, 71% adults). Twenty-six patients were on mTOR inhibitors. Demographic data, TSC manifestations, presence, and outcomes in individuals with confirmed or suspected SARS-CoV-2 infection were evaluated. Health status and outcomes of all patients on mTOR inhibitors were assessed. One patient with severe TSC had polymerase chain reaction (PCR)-confirmed SARS-CoV-2 infection, was admitted to ICU, and died. Nine additional patients either met the definition of suspect case or presented with at least two of the most common symptoms of SARS-CoV-2 infection. All recovered fully. None of the patients treated with mTOR inhibitors for their underlying comorbidities was diagnosed with COVID-19, and those who showed suspicious respiratory symptoms recovered fully. This cohort study provides preliminary information on COVID-19 in people with TSC in Italy and suggests feasibility to systematically evaluate the role of mTOR inhibitors in SARS-CoV-2 infection.

Natural history of incidental sporadic and tuberous sclerosis complex associated lymphangioleiomyomatosis.

Lymphangioleiomyiomatosis (LAM) is a rare disease affecting women in childbearing age. A sporadic form (S-LAM) affecting previously healthy women, and a form associated with Tuberous Sclerosis Complex (TSC-LAM) are described. Some data suggested that TSC-LAM could be a milder disease compared to S-LAM. To investigate whether the different disease behavior is real or due to overdiagnosis of screened TSC women, we compared the natural history of S-LAM and TSC-LAM in patients with incidental diagnosis. Clinical, and functional data from 52 patients (23 with S-LAM and 29 with TSC-LAM) were analysed. At diagnosis functional impairment was mild without differences between groups [FEV1 % pred was 97% (88-105) and 94% (82-106) in TSC-LAM and S-LAM, respectively, p = 0.125]. Patients with S-LAM had less renal angiomyolipoma, and lower VEGF-D serum levels than TSC-LAM. There was no difference in the baseline extent of pulmonary cysts on CT scan and no difference in yearly rate of functional decline between TSC-LAM, and S-LAM patients [e.g. yearly rate of decline of FEV1 % pred was -0.51 (-1.59-2.24) and -0.90 (-1.92--0.42) in TSC-LAM and S-LAM, respectively, p = 0.265]. In conclusion, the natural history of TSC-LAM and S-LAM, when a potential selection bias due to screening in the latter group is balanced, is similar. Our study suggests that the prevalence of S-LAM can be significantly underestimated due to a tendency to diagnosis more frequently patients with more severe impairment, without identifying several ones with asymptomatic disease.

The efficacy and safety of pharmacological treatments for lymphangioleiomyomatosis.

BACKGROUND: Lymphangioleiomyomatosis (LAM) is a rare, low-grade multisystem neoplastic disease. Most LAM patients are at a high risk of losing lung function at an accelerated rate and developing progressive dyspnea. Recently, several studies have reported their experience with pharmacological treatments for LAM. Therefore, we conducted a systematic review and meta-analysis to assess the efficacy and safety of these therapies. METHODS: PubMed (Medline), EMBASE, Cochrane Library, Web of Science and EBSCO Host were searched (until March 31, 2019) for eligible prospective studies regarding LAM patients treated with pharmacological treatments. Random effect models were used for quantitative analysis. RESULTS: Fourteen prospective studies regarding five pharmacological treatments (including sirolimus, everolimus, doxycycline, triptorelin, and a combination therapy of sirolimus and hydroxychloroquine) were enrolled in our systematic review, and ten of them were used for the meta-analysis. Seven prospective studies reported that sirolimus was effective at improving or stabilizing lung function and alleviating renal angiomyolipoma (AML) in LAM patients. Subsequent quantitative analyses showed that during sirolimus treatment, the pooled values of lung function and 6-min walk distance (6MWD) were not significantly changed (P > 0.05), with the pooled response rate of AML being 0.62 (95% confidence intervals [CIs]: 0.43 to 0.82, I2 = 65%). Regarding everolimus, three prospective studies reported similar effects to those of sirolimus with regard to preserving lung function and reducing AMLs. The meta-analysis showed that the changes in lung function during everolimus treatment were not statistically significant (P > 0.05), while the pooled response rate of AML was 0.78 (95% CI: 0.68 to 0.88, I2 = 8%). Neither the qualitative nor the quantitative results confirmed the benefits of doxycycline or triptorelin treatment, and the effects of the combination therapy were unclear in LAM patients. Most of the adverse events during pharmacological treatments were low or moderate grade and tolerable. CONCLUSIONS: Overall, sirolimus and everolimus were recommended for the treatment of LAM because they could stabilize lung function and alleviate renal AML. Doxycycline and triptorelin were not recommended for the treatment of LAM because no beneficial outcomes were consistently observed. The efficacy and safety of combination therapy remain to be further explored.

Favorable survival even with high disease-specific complication rates in lymphangioleiomyomatosis after lung transplantation-long-term follow-up of a Japanese center.

BACKGROUND: Lung transplantation (LT) is a reliable therapeutic option for end-stage pulmonary lymphangioleiomyomatosis (LAM). Long-term outcome of LAM recipients after LT remains unknown. The aim of this study was to describe the outcomes of LT for LAM with a long-term follow-up, comparing those for other diseases in the same period. METHODS: We retrospectively reviewed consecutive 145 LT recipients between 1998 and 2015 at Okayama University Hospital with minimum 3-year follow-up. RESULTS: Twelve LAM recipients including nine sporadic-LAM and three tuberous sclerosis complex -LAM were identified. Nine of 12 underwent bilateral LT including four living-donor lobar LT. There was no significant difference in overall survival between the two groups. (P = 0.15). Chronic lung allograft dysfunction free survival rate in LAM compared with other diseases tended to be better (P = 0.058). However, the rate of requiring hemodialysis was significantly higher in LAM recipients than in the recipients of other diseases (P = 0.047). Notably, 8 of 12 (67%) LAM patients encountered LAM-related complication including chylothorax and pneumothorax, seven (58%) had proliferative diseases consisting of renal angiomyolipoma and recurrent LAM. Nine patients required mTOR inhibitors for LAM-related problems, contributing to improved control of LAM-related problems. While all nine recipients of bilateral LT have still survived, two patients died of diseases in their native lungs and one required re-LT among three recipients of single LT. CONCLUSION: Although the rates of LAM-related complications were unexpectedly high in the long term, LT is a feasible therapeutic option for patients with advanced pulmonary LAM.

Air travel and incidence of pneumothorax in lymphangioleiomyomatosis.

BACKGROUND: Pulmonary lymphangioleiomyomatosis (LAM) is a rare disease of women characterized by multiple lung cysts leading to respiratory insufficiency and frequent pneumothorax (PT). Air travel (AT) could increase the risk of PT in LAM through rupture of subpleural cysts induced by atmospheric pressure changes in aircraft cabin. To determine whether AT increases the risk of PT in LAM, we performed a retrospective survey of members of European LAM patient associations. A flight-related PT was defined as occurring ≤30 days after AT. RESULTS: 145 women reported 207 PT. In 128 patients with available data, the annual incidence of PT was 8% since the first symptoms of LAM and 5% since LAM diagnosis, compared to 0.006% in the general female population. Following surgical or chemical pleurodesis, the probability of remaining free of PT recurrence was respectively 82, 68, and 59% after 1, 5 and 10 years, as compared to only 55, 46 and 39% without pleurodesis (p = 0.026). 70 patients with available data performed 178 AT. 6 flight-related PT occurred in 5 patients. PT incidence since first symptoms of LAM was significantly higher ≤30 days after AT as compared to non-flight periods (22 versus 6%, risk ratio 3.58, confidence interval 1.40-7.45). CONCLUSIONS: The incidence of PT in LAM is about 1000 times higher than in the general female population, and is further increased threefold after AT. Chemical or surgical pleurodesis partly reduces the risk of PT recurrence in LAM.

Incidental lymphangioleiomyomatosis in the lymph nodes of gynecologic surgical specimens.

OBJECTIVES: Incidentally discovered lymphangioleiomyomatosis (LAM) in sampled lymph nodes are infrequent but intractable issues for gynecologists. The aims of this study were to elucidate the prevalence of incidental nodal LAM in a consecutive cohort of gynecologic surgical specimens from Japanese patients, to document clinicopathological features of nodal LAM cases, and to investigate the association between the subsequent development of pulmonary LAM and tuberous sclerosis complex (TSC). STUDY DESIGN: We retrospectively reviewed 1732 consecutive Japanese patients who underwent gynecologic surgery with lymph node sampling in the National Cancer Center Hospital between January 2004 and April 2017. The pathological diagnosis of LAM was performed by pathologists. Clinicopathological data were obtained from patients' electronic medical records. RESULTS: We found that 0.46% (8/1732) of gynecologic surgical specimens with lymph node sampling showed incidental nodal LAM. The size of the lesions was less than 10 mm, and external iliac and obturator nodes were frequently affected. Although there has been no report of a case of incidental nodal LAM developing pulmonary LAM, we identified the first case of a 36-year-old woman who developed pulmonary LAM 7 years after the diagnosis of incidental nodal LAM. None of the 8 patients had a personal or family history of TSC. CONCLUSIONS: Our case brings attention to the risk of developing subsequent pulmonary LAM. To date, insufficient long-term follow-up data of young patients have hindered us from drawing a definite conclusion that patients with incidental nodal LAM are not at risk for subsequent pulmonary LAM. Future studies should collect and share long-term follow-up data to elucidate the true risk of developing pulmonary LAM in women with incidental nodal LAM.

Pulmonary hypertension in lymphangioleiomyomatosis: prevalence, severity and the role of carbon monoxide diffusion capacity as a screening method.

BACKGROUND: Lymphangioleiomyomatosis (LAM) is included within group 5 of the current PH classification (unclear multifactorial mechanisms). However, data regarding the occurrence of PH in LAM are scarce. The aims of the study were to describe the prevalence and characteristics of PH in a large cohort of LAM patients with different levels of severity, and to evaluate the role of echocardiography and carbon monoxide diffusion capacity (DLCO) as screening methods for PH in LAM. METHODS: One hundred five LAM patients underwent transthoracic echocardiography, pulmonary function tests (PFTs) and 6-min walk test (6MWT). Patients with a suspicion of PH on echocardiography, defined by the presence of estimated systolic pulmonary artery pressure (PAP) over 35 mmHg or PFT showing DLco below 40% of the predicted value, underwent right heart catheterisation to confirm the diagnosis of PH. RESULTS: Eight patients (7.6%) had PH confirmed on right heart catheterisation, six patients (5.7%) had a pre-capillary pattern and two patients (1.9%) had a post-capillary profile. Only one patient (1%) had mean PAP over 35 mmHg. Patients with PH had lower FEV1 and DLCO in PFTs and greater oxygen desaturation and dyspnea intensity during 6MWT compared with those without PH. In 63% of the patients with confirmed PH, the right heart catheterisation was performed based only on DLCO result. CONCLUSIONS: The prevalence of PH is low in LAM patients. Pulmonary hypertension in LAM is typically mild and significantly associated with pulmonary parenchymal involvement. Carbon monoxide diffusion capacity significantly improved the identification of PH in LAM patients.

TuberOus SClerosis registry to increase disease Awareness (TOSCA) - baseline data on 2093 patients.

BACKGROUND: Tuberous sclerosis complex (TSC) is a rare autosomal dominant genetic disorder. Many gaps remain in the understanding of TSC because of the complexity in clinical presentation. The TuberOus SClerosis registry to increase disease Awareness (TOSCA) is an international disease registry designed to address knowledge gaps in the natural history and management of TSC. Here, we present the baseline data of TOSCA cohort. METHODS: Patients of any age diagnosed with TSC, having a documented visit for TSC within the preceding 12 months, or newly diagnosed individuals were included. The registry includes a "core" section designed to record detailed background information on each patient including disease manifestations, interventions, and outcomes collected at baseline and updated annually. "Subsections" of the registry recorded additional data related to specific features of TSC. RESULTS: Baseline "core" data from 2093 patients enrolled from 170 sites across 31 countries were available at the cut-off date September 30, 2014. Median age of patients at enrollment was 13 years (range, 0-71) and at diagnosis of TSC was 1 year (range, 0-69). The occurrence rates of major manifestations of TSC included - cortical tubers (82.2%), subependymal nodules (78.2%), subependymal giant cell astrocytomas (24.4%), renal angiomyolipomas (47.2%), lymphangioleiomyomatosis (6.9%), cardiac rhabdomyomas (34.3%), facial angiofibromas (57.3%), forehead plaque (14.1%), ≥ 3 hypomelanotic macules (66.8%), and shagreen patches (27.4%). Epilepsy was reported in 1748 (83.5%) patients, of which 1372 were diagnosed at ≤ 2 years (78%). Intellectual disability was identified in 451 (54.9%) patients of those assessed. TSC-associated neuropsychiatric disorders (TAND) were diagnosed late, and not evaluated in 30-50% of patients. CONCLUSION: TOSCA is the largest clinical case series of TSC to date. It provided a detailed description of the disease trajectory with increased awareness of various TSC manifestations. The rates of different features of TSC reported here reflect the age range and referral patterns of clinics contributing patients to the cohort. Documentation of TAND and LAM was poor. A widespread adoption of the international TSC assessment and treatment guidelines, including use of the TAND Checklist, could improve surveillance. The registry provides valuable insights into the necessity for monitoring, timing, and indications for the treatment of TSC.

The effect of mTOR inhibitors on respiratory infections in lymphangioleiomyomatosis.

Lymphangioleiomyomatosis (LAM) is a destructive cystic lung disease. Mammalian target of rapamycin (mTOR) inhibitors are the primary treatment for LAM but it is unknown whether these immunosuppressing medications increase the risk for or the severity of respiratory infections in LAM patients.We searched multiple databases for original articles that reported the rate of respiratory infections in LAM patients treated with mTOR inhibitors or placebo. We calculated incidence rates for respiratory infections in these groups and incidence rate ratios for respiratory infections and severe respiratory infections in mTOR inhibitors treated versus placebo treated patients.11 studies were included. There were 294 patients in the treatment groups and 93 patients in the placebo groups. Among subjects in placebo arms, the incidence rate of respiratory infections was 58.8 per 100 patient-years (95% CI 35.3-82.3 per 100 patient-years). The incidence-rate ratio (IRR) for respiratory infection among treated subjects was 0.71 (95% CI 0.50-1.02; p=0.06 compared to placebo subjects). The IRR for severe respiratory infections among treated subjects was 1.56 (95% CI 0.43-8.55; p=0.52).We found that respiratory infections are common in patients with LAM. Importantly, treatment with mTOR inhibitors does not increase the incidence of these infections and may be protective.

Incidence of Pneumothorax in Patients With Lymphangioleiomyomatosis Undergoing Pulmonary Function and Exercise Testing.

Because pneumothorax is frequent in lymphangioleiomyomatosis, patients have expressed concerns regarding the risk of pneumothorax associated with pulmonary function or exercise testing. Indeed, pneumothorax has been reported in patients with lung disease after both of these tests. The aim of this study was to determine the incidence of pneumothorax in patients with lymphangioleiomyomatosis during admissions to the National Institutes of Health Clinical Research Center between 1995 and 2015. Medical records were reviewed to identify patients who had a pneumothorax during their stay at the National Institutes of Health. A total of 691 patients underwent 4,523 pulmonary function tests and 1,900 exercise tests. Three patients developed pneumothorax after pulmonary function tests and/or exercise tests. The incidence of pneumothorax associated with lung function testing was 0.14 to 0.29 of 100 patients or 0.02 to 0.04 of 100 tests. The incidence of pneumothorax in patients undergoing exercise testing was 0.14 to 0.28 of 100 patients or 0.05 to 0.10 of 100 tests. The risk of pneumothorax associated with pulmonary function or exercise testing in patients with lymphangioleiomyomatosis is low.

Women with TSC: Relationship between Clinical, Lung Function and Radiological Features in a Genotyped Population Investigated for Lymphangioleiomyomatosis.

The advent of pharmacological therapies for lymphangioleiomyomatosis (LAM) has made early diagnosis important in women with tuberous sclerosis complex (TSC), although the lifelong cumulative radiation exposure caused by chest computer tomography (CT) should not be underestimated. We retrospectively investigated, in a cohort of TSC outpatients of San Paolo Hospital (Milan, Italy) 1) the role of pulmonary function tests (PFTs) for LAM diagnosis, 2) the association between LAM and other features of TSC (e.g. demography, extrapulmonary manifestations, genetic mutations, etc.), and 3) the characteristics of patients with multifocal micronodular pneumocyte hyperplasia (MMPH). Eighty-six women underwent chest CT scan; pulmonary involvement was found in 66 patients (77%; 49% LAM with or without MMPH, and 28% MMPH alone). LAM patients were older, with a higher rate of pneumothorax, presented more frequently with renal and hepatic angiomyolipomas, and tended to have a TSC2 mutation profile. PFTs, assessed in 64% of women unaffected by cognitive impairments, revealed a lower lung diffusion capacity in LAM patients. In multivariate analysis, age, but not PFTs, resulted independently associated with LAM diagnosis. Patients with MMPH alone did not show specific clinical, functional or genetic features. A mild respiratory impairment was most common in LAM-TSC patients: In conclusions, PFTs, even if indicated to assess impairment in lung function, are feasible in a limited number of patients, and are not significantly useful for LAM diagnosis in women with TSC.

Lymphangioleiomyomatosis and multifocal micronodular pneumocyte hyperplasia in Japanese patients with tuberous sclerosis complex.

BACKGROUND: Pulmonary involvement in tuberous sclerosis complex (TSC) includes lymphangioleiomyomatosis (LAM) and multifocal micronodular pneumocyte hyperplasia (MMPH). This retrospective study investigated pulmonary involvement in Japanese TSC patients and pulmonary function testing in TSC-LAM. METHODS: The study subjects included 59 TSC patients (age range: 13-66, 15 males and 44 females). Female patients were divided into 3 groups (Group 1: symptomatic LAM, Group 2: asymptomatic LAM, Group 3: without LAM) and 3 cystic grades according to increasing cyst numbers on computed tomography images (patients without LAM, Grade 1 patients, and Grade 2+Grade 3 patients). The results of pulmonary function tests were compared among the groups and the grades. RESULTS: One male (6.7%) patient and 19 female (43.2%) patients were diagnosed with LAM and 7 male (43.2%) and 23 female (52.3%) patients were diagnosed with MMPH. Patients with multiple pulmonary nodules had higher rates of renal angiomyolipoma and history of seizures than patients without nodules. Although all 6 adolescent patients displayed no pulmonary symptoms, MMPH was found in 3 patients and LAM was found in a 13-year-old girl. Carbon monoxide diffusing capacity (DLco) differed significantly among the 3 groups and DLco and carbon monoxide diffusing capacity divided by the alveolar volume (DLco/VA) differed significantly among the 3 cystic grades. CONCLUSIONS: There was no difference in the prevalence of pulmonary involvement in TSC patients among countries. LAM and MMPH occur even during adolescence in TSC patients. DLco and the number of cysts are useful predictors of onset and progression of TSC-LAM.