Version May 2024
INTRODUCTION — Lymphangioleiomyomatosis (LAM) is a rare multisystem disorder that mostly afflicts women. The term sporadic LAM is used for patients with LAM who do not have tuberous sclerosis complex (TSC), while TSC-LAM refers to LAM that occurs in patients with TSC. The management of LAM is generally based upon supportive care, use of sirolimus to slow progression of respiratory impairment, and prevention or treatment of complications [1,2].
The management, monitoring, and prognosis of sporadic LAM and its complications are reviewed here. The epidemiology, pathogenesis, clinical presentation, and diagnostic evaluation of sporadic and TSC-LAM are discussed separately. (See "Sporadic lymphangioleiomyomatosis: Epidemiology and pathogenesis" and "Sporadic lymphangioleiomyomatosis: Clinical presentation and diagnostic evaluation" and "Tuberous sclerosis complex associated lymphangioleiomyomatosis in adults".)
GENERAL MEASURES — Given the complexities and multisystem nature of LAM, we encourage patient referral to centers with expertise in this disorder for shared care between LAM experts and local pulmonologists. (See 'Additional resources' below.)
Supportive care — Several supportive measures are useful in managing patients with LAM:
●Avoidance of cigarette smoking – Patients with LAM should be advised to avoid cigarette smoking and passive exposure to tobacco smoke, given the potential for accelerating disease progression (table 1). (See "Overview of smoking cessation management in adults" and "Pharmacotherapy for smoking cessation in adults" and "Behavioral approaches to smoking cessation".)
●Administration of COVID-19, influenza, and pneumococcal vaccines – Similar to patients with other chronic lung diseases, vaccination against common respiratory pathogens should be performed in all LAM patients (figure 1). (See "Standard immunizations for nonpregnant adults" and "Seasonal influenza vaccination in adults" and "Pneumococcal vaccination in adults" and "COVID-19: Vaccines".)
●Supplemental oxygen – Supplemental oxygen is indicated in those who desaturate (ie, pulse oxygen saturation [SpO2]) at rest (table 2), during exercise, and/or with sleep. While resting SpO2 is routinely performed during clinic visits by most subspecialists, clinicians should have a low threshold to perform nocturnal oximetry or a formal six-minute walk test to evaluate the need for oxygen supplementation. (See "Overview of pulmonary function testing in adults", section on 'Six-minute walk test'.)
One retrospective study of 25 patients with LAM and mild to moderate lung function impairment reported significant nocturnal desaturations in 56 percent of patients, despite a normal resting SpO2 [3]. While the long-term risk of isolated nocturnal desaturation is unknown, we prescribe supplemental oxygen for sleep-related hypoxemia when the SpO2 drops below 88 percent for more than 5 percent or at least five minutes of the sleep duration, the patient has symptoms or signs reasonably associated with desaturation (eg, pulmonary hypertension, erythrocytosis), and no other cause (eg, obstructive sleep apnea) is identified. (See "Long-term supplemental oxygen therapy" and "Portable oxygen delivery and oxygen conserving devices".)
●Exercise and pulmonary rehabilitation – We routinely refer symptomatic patients with LAM for pulmonary rehabilitation, particularly those whose activities are limited by dyspnea [4,5]. One study reported reduced physical activity in 34 women with LAM compared with healthy volunteers and age-matched women with chronic obstructive pulmonary disease (COPD) [4]. Another study of 40 patients with LAM reported rehabilitation was safe in those with a low physical activity level and led to improved exercise capacity, dyspnea, quality of life, and muscle strength [5]. (See "The benefits and risks of aerobic exercise" and "Pulmonary rehabilitation".)
●Nutrition – Patients with LAM should eat a healthy diet and maintain a normal weight. While traditionally women with LAM were advised to avoid eating foods containing phytoestrogens (eg, soy), there is no evidence that this strategy affects disease progression in LAM, and dietary restrictions based on the hormonal influences of food are not generally advised. A systematic review of the effects of soy and phytoestrogens in breast cancer concluded that soy does not have significant estrogenic activity in humans and is safe in the quantities consumed in a traditional Japanese diet [6]. (See "Malnutrition in advanced lung disease".)
●Psychosocial support – Many patients experience fear, anxiety, and depression during the course of their illness, which is often most pronounced soon after diagnosis. Proactive psychosocial support from clinicians, chaplains, mental health and palliative care providers, and LAM advocacy and support groups can help prevent debilitating mental health consequences. (See "Psychosocial issues in advanced illness" and "Palliative care for adults with nonmalignant chronic lung disease" and 'Additional resources' below.)
Bronchodilators and inhaled glucocorticoids — In patients with airflow obstruction on spirometry, particularly those with demonstrable reversibility, inhaled bronchodilator therapy may provide symptomatic relief [7,8], despite the absence of an effect on dynamic hyperinflation [7,9]. Some patients appear to respond better to inhaled beta-agonists and others to inhaled anticholinergic agents. An empiric trial of each is appropriate with a view to chronic maintenance therapy for patients with symptomatic benefit. The efficacy of inhaled glucocorticoids has not been formally examined. Their use is typically reserved for patients who are believed to have concomitant asthma. (See "An overview of asthma management" and "Beta agonists in asthma: Acute administration and prophylactic use" and "Role of muscarinic antagonist therapy in COPD".)
Minimizing risk of complications
Air travel — Patients should be assessed for the potential risk associated with an in-flight pneumothorax and/or oxygen desaturation. In general, most LAM patients can undertake air travel safely.
●Pneumothorax – Patients with LAM are reported to have a small but increased risk of spontaneous pneumothorax during flight (1 to 2 per 100 flights). Decisions regarding the safety of air travel are influenced by several factors including the burden of cysts, degree of lung function impairment, history of pneumothoraces, prior pleurodesis, and extent of cardiopulmonary reserve in the event of an in-flight pneumothorax. In general, air travel is considered to be safe in most patients with LAM [10,11]. However, patients with reduced pulmonary reserve or high-risk features (eg, high burden of cysts, severe lung function impairment, history of multiple pneumothoraces) may prefer to seek alternative modes of travel. Patients with unexplained or new onset chest pain or dyspnea should be evaluated with a chest radiograph to rule out pneumothorax prior to air travel. Additional details regarding air travel and pneumothorax are described separately. (See "Pneumothorax and air travel".)
This approach is based upon data from retrospective series:
•In one series of 281 patients with LAM, the risk of a new pneumothorax on chest radiograph or computed tomography (CT) was no different in those who traveled by air (3 percent, 1.1 per 100 flights) compared with those who traveled by land (2 percent, 0.5 per 100 trips) [10]. A new pneumothorax was more likely in patients with large cysts and more severe disease, regardless of the mode of travel. Over one-half of the patients had evidence of chronic pneumothorax.
•In a questionnaire-based evaluation derived from 276 patients with LAM who reported air travel (estimated total of 454 flights), most women traveled without serious adverse events [11]. However, a significant proportion reported air travel-related dyspnea (14 percent), chest pain (12 percent), pneumothorax (4 percent; most identified by chest radiograph), and oxygen desaturation (8 percent). The rate of pneumothoraces was 2.2 events per 100 flights.
•In another questionnaire-based study of LAM patients in the European Union, five patients reported a spontaneous pneumothorax from 178 flights, amounting to a per-flight pneumothorax risk of 2.8 percent. However, in contrast to the prior studies that focused on events in the immediate peri-travel period, any pneumothorax detected within 30 days of travel was deemed secondary to air travel in this study, leading to a higher estimate of the risk [12].
●Supplemental oxygen – When assessing the need for supplemental oxygen during flight, the principles of management should be similar to those with other lung diseases. (See "Evaluation of patients for supplemental oxygen during air travel", section on 'Pulmonary lymphangioleiomyomatosis' and "Pneumothorax and air travel".)
Exogenous estrogen — LAM exacerbations have been associated with the use of exogenous systemic estrogen (eg, birth control pills, hormone replacement, ovulation induction agents for assisted reproduction) (table 3), and exposure to these agents should be minimized (eg, for egg harvest) or avoided. Low-dose topical estrogen creams, tablets, and rings used for atrophic vaginitis are generally felt to be safe in survivors of breast cancer and, by extrapolation, in patients with LAM [13].
Pregnancy and birth control — Clinicians should inform women with LAM about the increased risks associated with pregnancy including pneumothorax, chylothorax, lung disease progression, and hemorrhage into angiomyolipomas (AMLs) [1,14-24]. Although some patients have tolerated pregnancy without long-term consequences, many patients do develop LAM-related complications, and there are no known factors that reliably predict risk. Because of the uncertainty, many women with LAM choose to avoid pregnancy. For patients who choose to become pregnant, those with excellent lung function and a stable disease course at baseline are better positioned to assume risk, while those with severe lung impairment or rapidly declining disease, recurrent pneumothorax or chylothorax, or a significant burden of AML may have more limited reserves and greater potential for complications.
This approach is based upon limited objective data regarding the effects of pregnancy on LAM disease course. Small retrospective series report that between one- and two-thirds of women with LAM have been pregnant at some point in their lifetime [20,25], but in most studies it is unclear if LAM was present during pregnancy. In a study of 16 pregnant women with LAM, the mean forced expiratory volume in one second (FEV1) decreased from 77 percent predicted before pregnancy to 64 percent predicted after pregnancy [26]. Diffusing capacity decreased from 66 to 57 percent predicted. Five patients developed pneumothorax (bilateral in four) during pregnancy, which was consistent with the 25 to 30 percent prevalence of pneumothorax during pregnancy noted in a survey-based assessment of women with LAM [24]. Mechanistic target of rapamycin (mTOR) inhibitors were withdrawn at or before pregnancy in the three patients for whom they were prescribed. Ten women underwent cesarean section while six had spontaneous vaginal delivery. After pregnancy, FEV1 continued to decline in many patients, 10 of whom required sirolimus treatment and one of whom required lung transplantation. This observational study affirms the above-mentioned assertions that pregnancy can accelerate the rate of disease progression in certain women with LAM.
For women who choose to avoid pregnancy, our approach to birth control is the following:
●Options for birth control – Selecting a method for contraception should be done in conjunction with a subspecialist; it is typically individualized and dependent upon patient preferences. Estrogen-containing oral contraceptives should be avoided since exogenous estrogens are thought to exacerbate the disease [27-30]. Potential options for contraception include abstinence, vasectomy of partner, tubal ligation, progesterone-only subcutaneous implants, intrauterine devices (IUDs; eg, copper or low-dose drug-eluting IUDs), oral or injectable progesterone, and barrier protection (table 3 and figure 2). (See "Contraception: Counseling and selection" and "Intrauterine contraception: Candidates and device selection" and "Contraception: Etonogestrel implant" and "Contraception: Progestin-only pills (POPs)" and "Pericoital (on demand) contraception: Diaphragm, cervical cap, spermicides, and sponge" and "External (formerly male) condoms".)
Emergency contraception (eg, levonorgestrel) should not be routinely used as the sole method of birth control; however, in rare circumstances the benefits of avoiding an unwanted pregnancy may outweigh the one-time use of emergency contraception. (See "Emergency contraception".)
●Pregnancy – For women who choose to become pregnant, comanagement with a maternal fetal medicine specialist is advised. The risk of fetal anomalies or spontaneous abortions is unknown but does not appear to be increased. Since sporadic LAM is not inheritable, genetic counseling is typically not necessary. (See "Overview of antepartum fetal assessment".)
Surveillance with pulmonary function testing is advised prior to pregnancy and as needed during gestation to investigate worsening symptoms in addition to ongoing monitoring for complications of LAM. While there is no consensus, the choice of delivering by cesarean section or vaginally (with or without regional anesthesia and instrumental assistance) should be individualized; however, in settings where anesthesia and assistance can be instituted, vaginal delivery is often the preferred option provided there are no other indications for cesarean section.
Successful pregnancies have been reported in women taking sirolimus (for LAM or for immune suppression following transplant) [31-33]. However, sirolimus has been reported to result in early fetal demise in animal studies and, as such, the use of sirolimus is typically avoided during pregnancy. It is unknown whether sirolimus is secreted in breast milk, and as such breast-feeding while taking sirolimus is not advised.
Others — Deep-sea diving, sky diving, and bungee jumping could theoretically increase the risk of pneumothorax, so patients are advised against participating in these activities.
Rare LAM cells have been isolated from the peripheral blood of untreated patients [34-36]. However, no reports of transmitting LAM via blood have been published to date and it is unclear whether or not patients with LAM can safely donate blood [37].
TREATMENT OF PULMONARY LAM — The key treatment for parenchymal lung disease due to sporadic LAM is inhibition of the mechanistic target of rapamycin (mTOR) signaling with sirolimus. In general, sirolimus is indicated for symptomatic patients with abnormal lung function (forced expiratory volume in one second [FEV1] <70 percent predicted), evidence of rapidly progressive disease, or problematic chylous accumulations. It is important to consider the baseline trajectory of illness in making treatment decisions (eg, postmenopausal women may have a slower rate of decline) because the drug has toxicities and continuous exposure is required for durable benefit. Lung transplantation may be the only option for patients with advanced LAM or in those with disease that is refractory to mTOR inhibitor treatment.
Several guidelines have been published [1,2,38]. Our strategy for the treatment of LAM is in accordance with the American Thoracic Society and Japanese Respiratory Society (ATS/JRS) Clinical Practice Guidelines [2] and French guidelines from the Orphan Lung Network [38] but differs slightly from that of the European Respiratory Society (ERS) [1] because sentinel publications regarding sirolimus were not available during the preparation of the ERS guidelines. Given the complexities and multisystem nature of LAM, we encourage consultation with or referral to centers with expertise in this disorder when treatment with mTOR inhibitors is being considered. (See 'Additional resources' below.)
Normal or mildly impaired lung function — For most patients with normal or mildly impaired pulmonary function, we suggest supportive measures, treatment of complications as they arise, and monitored observation, rather than treatment with sirolimus. While there is no agreed upon threshold, we consider those with a FEV1 ≥70 percent predicted as having mild disease and those who have a FEV1 within the standard confidence limits as having normal function. (See 'General measures' above and 'Treatment of complications' below and 'Monitored observation' below.)
Some exceptions exists:
●Regardless of lung function, we administer sirolimus to patients with LAM who also have evidence of complications known to be sirolimus responsive (eg, symptomatic chylous accumulations, AMLs >4 cm in diameter). (See 'Chylothorax and chylous ascites' below and 'Angiomyolipomas' below and 'Other lymphatic disease' below.)
●In those with normal or mildly impaired lung function, we also consider therapy in those with substantial disease burden or rapidly progressive disease. Thus, on an individualized basis, we and other experts occasionally administer sirolimus in a select group of patients who have normal or mildly reduced FEV1 when one or more of the following is present:
•Evidence of abnormal and/or progressive lung dysfunction due to LAM:
-Rapidly declining FEV1 (eg, FEV1 loss of greater than 100 mL per year based on three or more separate post bronchodilator measurements over 12 to 18 months)
-Elevated residual volume (>120 percent predicted) sufficient to impact symptoms or vital capacity
-Reduced diffusing capacity for carbon monoxide (DLCO; <lower limit of normal)
-Heavy burden of cysts (ie, cysts involving more than one-third of the lungs)
•Evidence of abnormal gas exchange thought to be due to LAM:
-Exercise-induced desaturation (saturation drops by 4 percent or more with ambulation)
-Resting hypoxemia (partial arterial pressure of oxygen <70 mmHg; 9.3 kPa)
When considering sirolimus treatment in patients with mild LAM, clinicians should be aware that the evidence to support it is based on extrapolation from a sicker LAM population and the rationale that the potential benefits of early rather than late therapy outweigh the risks of drug-induced toxicity. A discussion with the patient is critical so that a shared, well-informed decision can be made regarding therapy. A randomized, multicenter trial to determine the efficacy of early, low-dose sirolimus administration in patients with normal or mildly reduced FEV1 is in progress (Multicenter Interventional LAM Early Disease [MILED] Trial, NCT03150914). (See 'Sirolimus (first line)' below.)
Monitored observation — Patients with sporadic LAM who have normal or mild lung function impairment are assessed by serial pulmonary function testing (PFT) at regular intervals to monitor the rate of disease progression and to assist in decision making with regards to treatment initiation with sirolimus. The role of serial measurements of vascular endothelial growth factor-D (VEGF-D) is unknown.
●Clinical evaluation and pulmonary functions tests – It is estimated that at least 12 to 18 months of quarterly FEV1 measurements are required to obtain an accurate slope of change [39]. Thus, we typically perform a formal clinical assessment and PFTs (postbronchodilator spirometry, lung volumes, and DLCO) at 6 and 12 months and postbronchodilator spirometry alone during interval visits at three and nine months. A prediction model can help estimate future lung function decline using a few easily obtained variables and may aid clinical decision making [40]. There is no agreed upon definition of fast versus slowly declining lung function, but in our practice, we consider those with an FEV1 decline of ≥100 mL per year (roughly three to four times the normal rate of FEV1 decline in adults) as "fast decliners" and consider initiation of sirolimus in this subgroup. In contrast, if lung function declines slowly or is stable, testing intervals can be extended to every 6 or 12 months until a definite indication to treat with sirolimus is reached. (See 'Normal or mildly impaired lung function' above and 'Moderate to severe lung function impairment' below.)
●CT – There is no consensus with regards to performing routine serial high-resolution CT (HRCT) chest in patients with LAM. The potential health risk of cumulative radiation exposure (1.5 to 7 millisievert [mSv] per examination) is weighed against the likelihood that repeat imaging will change management. Thus, for sporadic LAM patients with normal or mildly reduced lung function, we obtain additional HRCT only to investigate new symptoms suggestive of disease progression or complications.
Most centers possess the ability to perform a low-dose chest CT, similar to that performed for lung cancer screening [41]. Using this protocol, radiation exposure from a CT scan can be reduced by approximately 50 percent compared with HRCT and resolution is likely adequate for disease monitoring purposes in most patients. CT radiation dose can be lowered to 0.4 mSv (dose equivalent to that from posteroanterior and lateral chest radiography) using model-based iterative reconstruction techniques without compromising the accuracy of LAM cyst quantification [42]. However, the technology and expertise for this type of dose reduction procedure is not yet available at most centers. It is important to note that the utility of low-dose CT chest for disease monitoring in patients with LAM, and other cystic lung diseases, has not been systematically evaluated. Monitoring of AMLs is discussed separately. (See "Renal manifestations of tuberous sclerosis complex", section on 'Treatment' and 'Angiomyolipomas' below.)
●VEGF-D – VEGF-D should be measured at baseline, if not already performed during the diagnostic evaluation. This approach is based upon evidence that baseline levels of serum VEGF-D may predict decline off therapy and response to sirolimus [43-45]. These data are discussed below. (See 'Prognostic factors' below.)
Moderate to severe lung function impairment — For most patients with sporadic LAM who have moderate to severe lung function impairment, as defined by an FEV1 <70 percent predicted, we recommend treatment with sirolimus rather than observation. Everolimus is an alternative in those who do not tolerate sirolimus. Both agents belong to the mTOR inhibitor family, and sirolimus (also known as rapamycin) has been approved for the treatment of LAM by the US Food and Drug Administration (FDA), the European Medicines Agency, and regulatory agencies in many other countries [46]. While sirolimus stabilizes lung function and improves some measures of quality of life and functional performance, it is a suppressive rather than curative therapy and lung function decline typically resumes once the drug is stopped [47].
In postmenopausal women who do not have historical lung function data available, but who have a reasonable respiratory reserve (eg, FEV1 >50 percent predicted), or in asymptomatic patients, it may be appropriate to establish a baseline rate of disease progression using serial lung function measurements over a 6-to-12 month period prior to initiating sirolimus. The rationale for this approach is that the trajectory of lung function decline is typically slower in this population, although direct evidence to support this approach is limited.
Sirolimus (first line)
Dose and duration
●Dose
•Initial dosing – We typically start sirolimus at 1 mg orally once daily and measure trough levels (20 to 28 hours after the last dose) 7 to 14 days after drug initiation, targeting a serum level of ≤10 ng/mL. In the pivotal randomized trial that demonstrated the efficacy of sirolimus (MILES trial), sirolimus levels were titrated to a range between 5 and 15 ng/mL, the median sirolimus level in MILES was 7 ng/mL, and levels in excess of 10 ng/mL were rare [47]. While many experts initiate sirolimus at 2 mg/day, following the approach employed in the only randomized trial that has demonstrated efficacy [47], we find that 1 mg/day is often sufficient to stabilize lung function [48], even when trough sirolimus levels are below 5 ng/mL. However, in patients who are declining very rapidly (ie, >100 mL/year) or have limited reserves, we feel it is prudent to start with 2 mg/day and consider titrating back to 1 mg/day once stability is achieved. Additional support for targeting a trough level of <10 ng/mL, rather than the 5 to 15 ng/mL classically published in literature, has also been described in patients taking sirolimus following lung transplantation [49,50].
•Subsequent dosing – Subsequent dosing varies depending upon several factors, such as clinical response, adverse effects, drug interactions, and intercurrent illnesses. We only escalate the sirolimus dose beyond 1 mg daily in patients who fail to achieve the desired clinical response, regardless of whether the trough sirolimus level achieves a predetermined target. Our philosophy is that when administering potentially life-long therapy to young women, it is prudent to use the lowest effective dose to optimize long-term safety. In contrast, we often decrease the dose, transiently or permanently, in patients experiencing adverse effects that affect patient safety, comfort, quality of life, or compliance. Sirolimus should be held temporarily (ie, one to two weeks before and one to two weeks after) for intercurrent illnesses involving fever or deep infection and for elective surgeries due to its immunosuppressant and delayed wound-healing effects. Evidence to support this dosing strategy and monitoring for adverse effects and a clinical response are discussed below. (See 'Efficacy' below and 'Monitoring adverse effects' below and 'Monitoring clinical response' below.)
●Duration – Sirolimus is a suppressive rather than curative therapy; upon discontinuation, lung function decline generally resumes at pretreatment rates. Thus, we typically continue sirolimus indefinitely, or for as long as it is tolerated, and try to minimize interruptions. Our experience has been that sirolimus has a favorable safety profile and results in continued stabilization of lung function in most patients [47,51-54]. An observational study (MIDAS, NCT02432560) is ongoing and aims to investigate the long-term safety and efficacy of sirolimus in patients with LAM. Data to support this strategy are discussed below. (See 'Efficacy' below.)
Whether or not sirolimus should be discontinued after menopause, a life transition that can be associated with a reduction in the rate of lung function decline, is unknown. Consideration of a trial of discontinuation involves shared decision making with the patient and vigilant monitoring off therapy.
Efficacy — Support for the use of sirolimus in this population is based upon one randomized study [47] that is corroborated by smaller observational studies, post hoc data, and clinical experience [36,45,47,48,51,52,55-60]. Data that support sirolimus efficacy for parenchymal disease in LAM are discussed in this section, while data that support the use of sirolimus in lymphatic disease are discussed below. (See 'Other lymphatic disease' below.)
●The effect of sirolimus on lung function was compared with placebo in a randomized trial of 89 patients with moderate to severe lung function impairment (FEV1 <70 percent predicted) due to LAM (MILES) [47]. Sirolimus was initially administered orally at 2 mg/day and adjusted to maintain a blood trough level between 5 and 15 ng/mL. After 12 months, the FEV1 was stable in the sirolimus group, but had declined in the placebo group (+1 versus -12 mL/month); improvements in the forced vital capacity (FVC; +8 versus -11 mL/month), functional residual capacity, quality of life, and functional performance were also noted in the sirolimus group compared with placebo. However, DLCO and six-minute walk distance did not improve. Patients were followed off treatment for an additional 12 months, during which time pulmonary function in the sirolimus group declined at the same rate as that in the placebo group.
Importantly, there was considerable variation in the response to sirolimus with some patients exhibiting significant improvements in lung function and a smaller proportion who continued to decline on therapy, albeit at a slower rate than placebo. In a post hoc analysis of the MILES trial, patients who had an elevated baseline VEGF-D declined more rapidly on placebo and had a more favorable physiologic response to sirolimus [43,45]. (See 'Prognosis' below.)
●Low-dose regimens may also confer similar improvement in lung function comparable with those reported in MILES. As an example, one case series of 15 LAM patients reported that sirolimus administered to target a trough ≤5 ng/mL resulted in improved FEV1 (-115 versus +128 mL/year) and FVC (-101 versus +190 mL/year) when compared with rates recorded prior to therapy [48]. Mean sirolimus trough levels of as low as 2 ng/mL were associated with disease stability; our clinical experience with the efficacy of low-dose sirolimus is similar.
●Data suggest that the effect is maintained while on long term sirolimus and may lead to improved survival [52,54,60]. One retrospective study reported an eight-year cumulative survival rate of 90 percent in patients treated with sirolimus compared with 78 percent in those not taking sirolimus despite worse baseline lung function and symptoms in the sirolimus treatment group (eg, FEV1 64 versus 86 percent) [60]. In a retrospective series of 12 patients with LAM followed for up to five years on sirolimus, a significant reduction in the annual rate of decline in FEV1 (+0.3 versus -1.4 percent predicted) and annual increase in cyst size (0.3 versus 1.8 percent) was reported [52]. Similarly, an open-label study of sirolimus administered for two years in 63 women with LAM reported overall stabilization of FEV1 and FVC and improvement in lung function [54]. The safety profile was favorable in each of these studies.
●Limited data report that patients with a rapid decline in lung function also benefit. Among those with rapidly declining FEV1 (>3 percent predicted per year) or diffusion capacity (>5 percent predicted per year) prior to therapy, sirolimus therapy at doses similar to those in MILES resulted in stabilization or improvement in these parameters when administered for up to 5.4 years (mean 2.6 years) [51]. However, resolution of chylous effusions on sirolimus in some patients may have resulted in overestimation of the effect of sirolimus on FEV1 slope before and after treatment initiation. (See 'Other lymphatic disease' below.)
●A post-hoc analysis of the MILES data has shown that sirolimus is an effective therapy for LAM regardless of underlying menopausal status (pre- versus postmenopausal), race (Asian versus White), LAM subtype (tuberous sclerosis complex [TSC] versus sporadic), baseline FEV1, or the presence or absence of reversible airflow obstruction [45].
The mechanism of action of sirolimus in LAM relates to its activity as an inhibitor of the mTOR complex, which is inappropriately activated by loss of TSC gene function in LAM (figure 3). A few studies have reported a reduction of LAM cells in both blood and on tissue biopsy in response to therapy [34,61]. Detailed discussion of mTOR and the pathogenesis of LAM is provided separately. (See "Sporadic lymphangioleiomyomatosis: Epidemiology and pathogenesis", section on 'Tuberous sclerosis gene mutations'.)
Monitoring adverse effects — Sirolimus is generally well tolerated, especially when administered in lower doses now commonly used for LAM; although some patients discontinue sirolimus due to side effects.
●Adverse effects – Adverse effects, which are generally dose-related, commonly include stomatitis, diarrhea, hyperlipidemia, dyspepsia, nausea, and acneiform rash. Less common adverse effects include lower extremity swelling, renal insufficiency, hypertension, drug interactions, infection, delayed wound healing, susceptibility to latent neoplasms, pneumonitis, allergies, and hematologic abnormalities (eg, anemia, thrombocytopenia, leukopenia, lymphopenia) [62]. Adverse effects from sirolimus tend to be most common in the few months following drug initiation and tend to decrease over time [45,54].
Mouth ulcers, acne, nausea, and diarrhea are usually easily treated with local therapies or over-the-counter medications. Topical applications of corticosteroids are the mainstay for treatment of mouth ulcers resulting from use of sirolimus [63-65]. Over-the-counter acne medications, usually containing benzoyl peroxide and/or salicylic acid, are reasonable first-line agents to treat acne resulting from sirolimus.
If hypercholesterolemia develops, it can usually be controlled with dietary modification and/or an oral statin. Profound hypertriglyceridemia has been reported in a few patients and can result in pancreatitis [66]. Anemia, leukopenia, lymphopenia, and thrombocytopenia have been reported but are rare at lower doses (eg, 1 mg/day) and usually not profound enough to warrant discontinuing the drug. (See "Low-density lipoprotein cholesterol-lowering therapy in the primary prevention of cardiovascular disease" and "Hypertriglyceridemia in adults: Management".)
Drug interactions can alter sirolimus levels (eg, antihypertensives, antibiotics, antiseizure medications); in such cases, remeasuring trough levels after 7 to 14 days on new medications with known interactions or using an alternative medication without interaction is prudent. A list of interactions can be identified using the drug interactions program included within UpToDate.
Infections due to the immunosuppressant function of sirolimus are a concern. However, one review of 11 studies reported that although infections occurred in patients treated with sirolimus, there was no statistical difference in the rate of respiratory infections, including severe infections when compared with placebo [67]. In addition, some studies suggest that mTOR inhibitors may actually enhance immunity in older adults and reduce viral infections [68,69].
Rare but serious side effects include pneumonitis and latent neoplasms (eg, lymphomas). Sirolimus pneumonitis did not occur in the MILES trial [47] but has been reported as a rare occurrence in other trials and case reports [54]. Sirolimus pneumonitis is typically reversible with either dose reduction or discontinuation. In cases where respiratory failure develops, corticosteroid therapy has been used to accelerate resolution [54]. Risk of latent malignancy is a class effect of immunosuppressant therapies but remains only a theoretical risk in the case of monotherapy with mTOR inhibitors since it has not been reported in LAM patients to our knowledge.
The optimal approach to detecting sirolimus-associated opportunistic infections or inflammatory pneumonitis is unknown. In general, these are rare events (<1 percent). We do not routinely perform surveillance chest CT scans but rather obtain chest imaging based upon development of symptoms of cough, shortness of breath, or fever. We do not generally prescribe prophylactic antibiotics to prevent opportunistic infections such as Pneumocystis jirovecii pneumonia (PJP) unless patients have other immunosuppressive conditions or treatments, such as poorly controlled diabetes, an underlying immunodeficiency disorder, or chronic steroid use.
Allergies to sirolimus are uncommon but can be life threatening. Desensitization regimens have been employed in some cases [70].
●Laboratory monitoring – We measure complete blood counts, fasting lipids and glucose, liver and renal function, and urine protein at baseline, and this panel plus sirolimus trough levels monthly for three months and then at three month intervals for the first year [47]. For those on 2 mg of sirolimus or higher, we generally continue obtaining these laboratory tests every three months indefinitely. In patients on low-dose sirolimus (<2 mg/day) who have no adverse effects over the first 12 months of therapy, we often extend the interval for laboratory studies to twice per year.
Monitoring clinical response — Patients should be assessed for adverse effects of sirolimus within the first two to four weeks and periodically thereafter (see 'Dose and duration' above and 'Monitoring adverse effects' above). Once desired levels have been achieved and the drug is demonstrated to be well tolerated, patients should also be clinically assessed for a symptomatic and physiologic response. Our approach is the following:
●Pulmonary function tests – Postbronchodilator spirometry (FEV1 and FVC) is typically obtained every three to six months, and full PFTs including DLCO and lung volumes should be obtained at least once per year. Reduction in the rate of decline in spirometric values relative to those measured prior to treatment is the primary metric of treatment response and should be plotted in all patients. In treated patients with limited pretreatment lung function data, we consider rates of FEV1 decline <50 mL/year to represent disease stabilization. Although diffusion capacity is not known to be improved by sirolimus, it should be measured since disease progression can occasionally manifest as reduction in DLCO disproportionate to spirometric values.
●Imaging – We typically do not perform routine chest CT scans to follow disease progression or treatment response, although practice varies considerably. Our approach is based upon the avoidance of cumulative radiation exposure and the lack of evidence to support CT as a validated radiologic biomarker. However, we perform chest CT in those with an atypical course or features and for other clinical indications (eg, a precipitous decrease in PFTs, suspected pneumonitis, or radiographically occult pneumothorax). CT evidence of reduced gas trapping and changes in lung texture surrounding cysts have been reported as outcomes of sirolimus therapy [71-73], but further study is needed to determine whether quantifying lung volumes or cyst volume ("cyst volume percent"), using standard- or low-dose CT, is of clinical value [74].
In contrast, reduction in size of AMLs on abdominal imaging is a measurable response to sirolimus that some experts consider a therapeutic biomarker in patients with LAM. (See "Renal manifestations of tuberous sclerosis complex" and "Renal manifestations of tuberous sclerosis complex", section on 'Treatment'.)
●Laboratory – Although treatment with sirolimus results in a reduction in VEGF-D levels [45,47,75], further studies are needed to determine whether serial VEGF-D testing can be used to facilitate decisions regarding dose and duration of therapy or as a surrogate biomarker to predict future response to therapy. We generally obtain baseline VEGF-D levels prior to initiating sirolimus. While there are no guidelines on the measurement of VEGF-D levels while on treatment with sirolimus, we typically obtain serum VEGF-D levels three months after starting sirolimus in order to assess the effect of treatment. Once serum VEGF-D has reached a nadir (typically three to four months following initiation of sirolimus), the VEGF-D monitoring intervals can be extended to every 12 months. If dose escalation is contemplated in the future, we believe that incremental reductions in VEGF-D upon up-titration of sirolimus can be used as a barometer of the degree of mTOR pathway suppression; that is, if VEGF-D drops further at higher doses, the pathway was incompletely suppressed. The potential value of VEGF-D as a prognostic marker is discussed below. (See 'Prognostic factors' below.)
VEGF-C is not routinely measured, although one study reported that VEGF-C levels decrease following treatment with sirolimus, and returned toward baseline when sirolimus is held, similar to the pattern of VEGF-D responses [76]. In another retrospective study, cancer antigen-125 (CA-125), which was elevated in 25 percent of patients with LAM, decreased following treatment with sirolimus [77]. However, it remains investigational as a marker of therapeutic response. Several other biomarkers are being investigated [78].
Everolimus (second line) — Anecdotally, rare patients who do not tolerate or respond to sirolimus may respond to everolimus. A theoretical advantage of everolimus over sirolimus is that it has a shorter half-life (30 versus 62 hours) [79], which may make it a more attractive therapy for those in whom more rapid washout is needed (eg, approaching lung transplantation or other surgery). However, whether this feature decreases the risk of dehiscence and delayed wound healing is unknown and no comparative trials have been performed.
●Dosing – While everolimus is not approved for sporadic LAM, the dose used in the only clinical trial was 2.5 mg mg/day increasing to 10 mg/day, targeting a trough level of 5 to 15 ng/mL [80]. There were significant side effects at the higher doses of everolimus, however, and in practice doses of greater than 5 mg/day are rarely used in sporadic LAM. As with sirolimus, many experts attempt to determine the lowest effective dose that maintains lung function stability by starting at a low dose and titrating the drug over time to the lowest level that maintains stability in postbronchodilator FEV1 measured every three months or so. Dose equivalence studies for sirolimus to everolimus conversions have not been established for sporadic LAM, but organ transplant studies suggest a ratio of 1:1 to 1:2. (See "Tuberous sclerosis complex: Management and prognosis", section on 'Role of mTOR inhibitor therapy'.)
●Efficacy – Data that support everolimus use in LAM are derived from one open-label study in LAM patients as well as from studies of treatment of TSC-related tumors. Collectively, the results suggest that everolimus and sirolimus likely have similar efficacy:
•In a multicenter, open-label safety study, 24 women with pulmonary LAM were treated with everolimus (2.5 mg/day increasing to 10 mg/day) for 26 weeks, targeting a trough level of 5 to 15 ng/mL [80]. The FVC remained stable, while the FEV1 improved from baseline with a mean increase of 114 mL and the six-minute walk distance improved by 47 meters. Improvements in lung function were sustained during the extension phase (up to 60 weeks of treatment). Adverse events were similar to sirolimus; serious adverse events included peripheral edema, pneumonia, pneumonitis, cardiac failure, and Pneumocystis jirovecii infection. There were five patients who stopped the study drug due to adverse effects, all while taking the highest dose (10 mg/day). We do not endorse the routine use of everolimus at this dose in patients with LAM.
•Everolimus is approved for the treatment of AMLs, central nervous system tumors, and epilepsy due to TSC. Durable benefit with long-term administration (eg, greater than two years) in TSC has been described [81]. (See 'Other lymphatic disease' below and "Renal angiomyolipomas (AMLs): Management" and "Tuberous sclerosis complex: Management and prognosis", section on 'Role of mTOR inhibitor therapy'.)
Other — For patients who do not respond to or who cannot tolerate the mTOR inhibitors, sirolimus or everolimus, options are limited to supportive care, treatment of complications, clinical trials, and lung transplantation. Although not routinely recommended, hormonal manipulation (eg, gonadotropin-releasing hormone [GnRh] agonists, aromatase inhibitors) is sometimes administered in mTOR inhibitor refractory or intolerant patients, especially those who have symptoms or complications that are exacerbated in a cyclical manner during the menstrual cycle [2]. (See 'Statins, doxycycline, hormone manipulation, hydroxychloroquine, celecoxib, resveratrol' below.)
Refractory disease — Some patients (probably less than 10 percent) continue to have progressive lung function decline despite the use of sirolimus. In this population, alternative explanations for lack of treatment response such as those listed below should be ruled out. (See 'Investigating progressive dyspnea' below.)
For those with progression due to worsening parenchymal disease, options include increasing the dose of sirolimus toward the upper end of the therapeutic range (ie, to serum levels of 10 to 15 ng/mL), a trial of substitution with everolimus, participation in clinical trials, and referral for lung transplantation. Although not routinely recommended, hormonal manipulation (eg, GnRh agonists, aromatase inhibitors, etc) is sometimes attempted, especially in those with menstrual cycle related variation in respiratory symptoms. Choosing among these options is dependent upon factors including patient preference and pulmonary reserve. (See 'Clinical trials' below and 'Lung transplantation' below and 'Everolimus (second line)' above and 'Statins, doxycycline, hormone manipulation, hydroxychloroquine, celecoxib, resveratrol' below.)
Clinical trials — Several clinical trials for LAM patients involving novel agents or combination therapies involving mTOR inhibitors and other agents have either been completed or are in progress. Detailed information regarding these studies can be accessed at Clinicaltrials.gov or The LAM Foundation website. Examples of investigational therapies include:
●Interferon-gamma or beta
●Anti-estrogen-tamoxifen [82]
●Promoters of autophagy (eg, hydroxychloroquine) [83]
●Matrix metalloproteinase inhibitors (eg, doxycycline) [84]
●Tyrosine kinase inhibitors (eg, saracatinib, imatinib)
●Inhaled sirolimus
●Prostaglandin inhibitors (Celecoxib or aspirin) [85]
●Statins (Simvastatin) [86]
●Resveratrol [87]
Lung transplantation — Patients with LAM may eventually require lung transplantation because of progressive respiratory failure. Selection criteria and lung transplantation type are similar to those for other chronic lung diseases. The presence of a renal AML, other complications of LAM, prior pleurodesis [88], or TSC are not generally considered to be contraindications to lung transplantation. The outcomes following lung transplantation in LAM appear to be better than patients with other chronic lung diseases [89]. (See "Lung transplantation: An overview".)
●Referral – While firm criteria for referral for lung transplantation evaluation have not been set, reasonable thresholds include New York Heart Association (NYHA) functional class III or IV (ie, symptoms with minimal exertion or severe limitation with symptoms at rest), rapidly progressive respiratory impairment, FEV1 <30 percent of predicted, and hypoxemia at rest. (See "Lung transplantation: General guidelines for recipient selection", section on 'General guidelines'.)
●Outcomes – Several series have reported results of lung transplantation for LAM [90-99]. The largest series analyzed outcomes in 134 LAM patients registered with the United States United Network for Organ Sharing (UNOS) who underwent lung transplantation between January 2003 and June 2017 [89]. The majority of patients (109/134, 81 percent) underwent bilateral sequential lung transplantation. The median time spent on the transplant wait list was 257 days, which was reduced to 148 days after the introduction of the lung allocation score in 2005. The median post lung transplant survival in LAM was 12 years, with 1-, 5-, and 10-year survival rates of 94, 73, and 55 percent, respectively. These survival rates exceed those of other disease groups transplanted in the same time frame (p<0.0001). Similar post-transplantation survival outcomes have been reported from a study evaluating 57 LAM patients who underwent lung transplantation in Japan, with 1-, 3-, and 5-year survival rates of 87, 82, and 74 percent, respectively [100].
Lung function and quality of life after transplant are improved compared with patients with advanced LAM [93]. The main causes of death after transplant are similar to other lung diseases and include primary graft dysfunction (early) and infection and bronchiolitis obliterans (late) [89]. (See "Primary lung graft dysfunction" and "Lung transplantation: An overview".)
Disease-related complications in one study of 34 patients included [90]:
•Extensive pleural adhesions in 18 patients, leading to intraoperative hemorrhage in four patients.
•Pneumothorax in the native lung in 6 of the 27 patients who received a single lung transplant.
•Postoperative chylothorax in three patients.
•Recurrent LAM in the allograft occurred in one patient; this complication has also been noted in other reports [95,99,101,102]. Recurrent LAM in the transplanted lung manifests as cellular aggregates derived from recipient cells, suggesting hematogenous migration of LAM cells as a mechanism of recurrent disease [101]. This metastatic mechanism is also supported by the relative absence of cystic change in an oligemic lung segment of a LAM patient with otherwise diffuse cystic lung disease [103].
●Management of sirolimus before and after transplant – Special considerations regarding sirolimus and lung transplantation should be noted (these apply primarily to the United States transplantation procedures):
•Pretransplant – Once listed for lung transplant, discontinuation of sirolimus is preferred by many transplant experts due to a potential increased risk of anastomotic dehiscence [104,105], which is included in a boxed warning issued by the FDA.
However, this practice, which often leads to rapid deterioration in lung function, has been challenged by some experts since the cases of anastomotic dehiscence that led to the boxed warning occurred when sirolimus was administered in the postoperative period and at levels higher than those typically used for LAM [106]. Thus, some transplantation experts support the use of low-dose sirolimus in patients on the waitlist based upon the rationale that sirolimus will wash out completely within five to seven days after the drug is discontinued on the day of surgery, three to five weeks before the period when most historic episodes of wound dehiscence occur (at approximately five to six weeks) [105]. Everolimus has a shorter half-life and washes out in approximately three to four days once the drug is held, leading some experts to recommend a switch to that agent in listed patients. In support of that approach, everolimus has been successfully administered up to the time of transplant in a small number of patients with idiopathic pulmonary fibrosis without occurrence of subsequent bronchial dehiscence [107]. The potential benefits of continuing mTOR inhibitors up until the time of transplantation were also endorsed by the International Society for Heart and Lung Transplantation guidelines [108], and data indicate that >25 percent of transplant centers allow waitlisted patients to remain on mTOR inhibitors [109].
•Posttransplant – Sirolimus and everolimus should not be used in the posttransplant period until wound healing is complete (usually at least several months after surgery). When planning antirejection therapies, we recommend that the posttransplant immunosuppressant regimen be optimized for prevention of rejection without prioritizing routine use of sirolimus or everolimus for prevention of recurrence. The rationale for this approach is that recurrence of LAM is rare and does not typically threaten graft function [97,98,110] and that mTOR inhibitors are not typically considered first-line antirejection therapies.
However, sirolimus has been successfully used for treatment of new onset chylothorax in patients with LAM at three months, and everolimus at four weeks, following lung transplant [111]. In some cases, very low-dose sirolimus (eg, 0.5 mg/day) has been added on top of existing immunosuppressive regimens without replacing other agents for chylothorax or evidence of parenchymal recurrence. Several case reports also describe the successful treatment of residual extrapulmonary disease (eg, lymphangioleiomyomas) posttransplant with the use of mTOR inhibitors [98,112,113]. The impact of such therapy on life expectancy and other posttransplant outcomes is unknown.
INVESTIGATING PROGRESSIVE DYSPNEA — The differential diagnosis for progressive shortness of breath in patients with LAM, whether on or off therapy, is broad, and the following etiologies should be considered and treated accordingly. Distinguishing among these entities is usually possible through clinical assessment and appropriate use of pulmonary function testing (PFT), CT of the chest or abdomen, and echocardiography. Etiologies include:
●Progressive pulmonary parenchymal disease due to LAM (see 'Treatment of pulmonary LAM' above)
●Drug-induced pneumonitis or immunosuppression-related infections due to sirolimus or everolimus (see "Pulmonary toxicity associated with antineoplastic therapy: Molecularly targeted agents", section on 'Rapamycin and analogs')
●Reversible airflow obstruction (see "An overview of asthma management")
●Pulmonary hypertension (see "Clinical features and diagnosis of pulmonary hypertension of unclear etiology in adults" and "Treatment of pulmonary arterial hypertension (group 1) in adults: Pulmonary hypertension-specific therapy")
●Pleuroperitoneal or pericardial chylous effusions (see 'Chylothorax and chylous ascites' below)
●Pulmonary parenchymal lymphatic congestion (see 'Other lymphatic disease' below)
●Pneumothorax (see 'Pneumothorax' below)
●Diaphragmatic impingement by large angiomyolipoma (AML) (see "Renal manifestations of tuberous sclerosis complex")
●Pulmonary embolism (see "Clinical presentation, evaluation, and diagnosis of the nonpregnant adult with suspected acute pulmonary embolism")
●Other non-LAM related etiologies (eg, asthma, heart failure)
Lymphatic congestion in the lungs is an ill-defined entity reminiscent of pulmonary edema described in case reports of patients with lymphatic disease [51,56]. It is thought to be caused by reflux of chylous fluid from the axial lymphatics into the pulmonary lymphatics.
TREATMENT OF COMPLICATIONS — Sporadic LAM is associated with a number of complications.
Pneumothorax — Approximately two-thirds of patients with LAM develop a pneumothorax during the course of their illness [25,114,115]. After the initial pneumothorax, the risk of recurrent ipsilateral, contralateral, or bilateral pneumothorax is high (approximately 70 percent; on average two to four recurrent episodes following the first event). Thus, we and others recommend ipsilateral pleurodesis after the first pneumothorax rather than waiting for a second event [88,114]. (See "Sporadic lymphangioleiomyomatosis: Clinical presentation and diagnostic evaluation", section on 'Pulmonary' and "Thoracostomy tubes and catheters: Indications and tube selection in adults and children" and "Treatment of secondary spontaneous pneumothorax in adults", section on 'Preventing recurrence and follow-up'.)
There is no consensus among experts regarding the optimal method of pleurodesis. Options include chemical pleurodesis (eg, tetracycline, betadine, bleomycin, talc) or surgical pleurodesis (usually via video-assisted thoracoscopy) with mechanical abrasion (partial or complete). Pleurectomy and talc pleurodesis are usually reserved for recurrences that follow a prior attempt at pleurodesis. Blebectomy should be avoided at the time of pleurodesis because it may lead to prolonged leak in patients with LAM (presumably because the staple lines involve diseased tissue). Choosing among these options should be individualized and typically varies according to the discretion of the treating pulmonologist and surgeon. Factors that should be taken into consideration include the ability of the patient to tolerate a recurrent pneumothorax or surgery, the presence of a persistent air leak, degree of lung re-expansion, and available expertise. Sirolimus should be held for at least one week prior to and two to four weeks following pleurodesis, to allow for optimal wound healing. We recommend that patients avoid air travel for at least one to two weeks following pleurodesis. Importantly, clinicians should be aware that prior pleurodesis, even bilateral talc pleurodesis, does not generally affect candidacy for future lung transplantation at most centers in the United States and Europe [88,114]. (See "Chemical pleurodesis for the prevention of recurrent pleural effusion" and "Treatment of secondary spontaneous pneumothorax in adults".)
Extrapolating from other populations, talc pleurodesis generally results in lowest rates of recurrence. However, we prefer video-assisted thoracoscopic surgery (VATS) guided mechanical abrasion as the initial choice, because it is less likely to cause a degree of pleural fusion that could complicate the removal of the native lung if transplant is required in the future. Talc and pleurectomy are associated with the highest risk of technical complications (eg, bleeding) during future transplantation due to the induction of intense inflammation and pleural symphysis (features that are also responsible for its superior efficacy). However, for those with repeated pneumothoraces or a refractory bronchopleural fistula, talc poudrage may be the most sensible option to avoid protracted attempts to achieve pleural symphysis with less aggressive approaches.
For unknown reasons, the recurrence rate after pleurodesis is generally higher in LAM than that in other lung diseases (approximately 35 percent versus <5 percent for chronic obstructive pulmonary disease [COPD] and many other lung diseases) and some patients may be left with a residual loculated pneumothorax. One questionnaire-based study of 193 patients with LAM reported recurrence rates of 66 percent after conservative therapy (ie, chest tube drainage), 27 percent after chemical pleurodesis, and 32 percent after surgical pleurodesis [114]. Among those who had undergone transplantation, over one-half had prior pleurodesis with one-third reporting pleural-related postoperative bleeding, albeit without an increase in length of hospital stay or mortality.
Patient perspectives on the management of pneumothorax may differ from those of clinicians. In a questionnaire-based study of 216 patients with LAM and pneumothorax, most patients felt that pleurodesis was more appropriate for a second rather than a first event [116]. Extensive pain appeared to be a major concern, and most patients felt that clinicians did not fully consider their discomforts or preferences.
General guidelines for management of pneumothorax from the United States and United Kingdom advise that pleurodesis be performed in those with underlying lung disease who have a first event and in those without underlying lung disease who develop two or more events [88,117,118]. However, the diagnosis of LAM is often not identified until a second or third pneumothorax has been discovered, resulting in a delay in appropriate therapy. We advocate for a low threshold to perform CT of the chest in young (25 to 54 years old), nonsmoking females presenting with a spontaneous pneumothorax (in whom the prevalence of LAM is estimated to be approximately 5 percent) [119,120]. Others estimate a much lower prevalence of LAM in this population and do not recommend CT screening [121].
Although pneumothoraces definitely occur in LAM patients on sirolimus, several studies have suggested a reduction in the rate of recurrent pneumothoraces with mechanistic target of rapamycin (mTOR) inhibitor therapy [122-124]. However, whether recurrent pneumothoraces constitute an indication to prescribe mTOR inhibitors is not clear.
Further detailed discussion of the management of pneumothorax is provided separately. (See "Chemical pleurodesis for the prevention of recurrent pleural effusion" and "Pneumothorax in adults: Epidemiology and etiology" and "Treatment of secondary spontaneous pneumothorax in adults" and "Clinical presentation and diagnosis of pneumothorax", section on 'Diagnostic imaging'.)
Chylothorax and chylous ascites — Sirolimus is the initial treatment of choice for symptomatic chylothorax, chylous ascites, lymphangioleiomyomas, and other lymphatic manifestations of LAM (see "Sporadic lymphangioleiomyomatosis: Clinical presentation and diagnostic evaluation", section on 'Lymphatic manifestations'). This approach is based upon several observational studies that report complete or near-complete resolution of chylous accumulations over months of therapy with sirolimus as well as the lack of consistent benefit from alternative therapies including resection, drainage and pleurodesis, thoracic duct ligation, dietary manipulation, and octreotide [36,48,51,56,113,125-129]. The dose and duration of sirolimus should be similar to that administered for pulmonary disease, although lower doses may also be effective. Importantly, time to resolution varies from 1 to 12 months, so in some instances, a temporary indwelling pleural catheter may be required to drain the pleural space until the full effect of the drug is realized. (See 'Sirolimus (first line)' above.)
●In a case series of 12 patients with LAM who had chylous effusions and received off-label sirolimus for up to 5.4 years (trough level 5 to 15 ng/mL), almost all of the patients experienced complete resolution of their effusion(s) [51]. Adverse effects were similar to those expected with mTOR inhibitors.
●Another case series showed that low-dose sirolimus (trough level, 5 ng/mL or less) was associated with resolution of chylothorax within one to five months in six of seven patients with LAM [48].
Dietary modification with a reduced fat, medium chain triglyceride-enriched diet is often recommended for management of chylothorax, but it is often unpalatable, associated with undesirable weight loss, and less likely to be effective when compared with sirolimus. We generally do not recommend dietary modifications in patients with chylous accumulations who are being treated with sirolimus. (See "Management of chylothorax".)
Drainage of chylous accumulations in the chest or abdomen is indicated for patients with respiratory compromise (eg, dyspnea, hypoxemia) or abdominal bloating and discomfort. Prolonged drainage (eg, more than two weeks) can result in nutritional depletion and should be limited to patients with significant symptoms from chylous accumulations. Refractory chylous ascites can result when lymphangioleiomyomas are manipulated; consequently, we do not recommend that these lesions be biopsied or resected in most cases.
In patients with chylous complications that are resistant to sirolimus, the optimal therapy is unknown. We typically obtain lymphatic imaging and refer to a specialized center with expertise in lymphatic disorders [130]. Although evidence is lacking to support one option over another, therapies include a trial of everolimus and alternative interventions, such as pleuro or peritoneovenous shunts [131,132], pleurodesis, somatostatin analogs or octreotide, omental patches [133,134], and thoracic duct manipulation (embolization or ligation). These options are discussed separately. (See "Management of chylothorax".)
While not generally recommended, anecdotal case reports suggest responses of chylous effusions to hormonal manipulation [135] or fibrin glue for chylous effusions following lung transplant [136]. (See 'Statins, doxycycline, hormone manipulation, hydroxychloroquine, celecoxib, resveratrol' below.)
Other lymphatic disease
●Patients with lymphangioleiomyomas – Biopsy or surgical resection of suspected or known lymphangioleiomyomas and engorged lymph nodes should be avoided due to the risk of prolonged leak, leading to refractory chylous ascites and/or nutrient depletion. Sirolimus appears to be effective for the treatment of even large lymphangioleiomyomas. One case series reported complete resolution of lymphangioleiomyomas in 11 patients treated with sirolimus (mean 2.6 years; trough level 5 to 15 ng/mL) [51] and another showed similar results in three patients treated with lower doses (trough levels 2.9 to 3.5 ng/mL) [128]. Asymptomatic, small lymphangioleiomyomas do not generally constitute an independent indication for sirolimus treatment.
Similar results have been reported with everolimus. Everolimus was administered in an open-label study to five patients with lymphangioleiomyomas complicating LAM [137]. All five experienced substantial shrinkage or complete resolution of the lymphangioleiomyomas. However, cessation of everolimus resulted in a recurrence in one patient.
●Patients with lymphadenopathy – Lymphadenopathy generally resolves or improves in patients with LAM who are treated with sirolimus for pulmonary disease, although there is a paucity of data supporting this observation and it is rare that lymphadenopathy would be an indication for treatment per se.
Angiomyolipomas — Most renal angiomyolipomas (AMLs) in patients with sporadic LAM do not require therapy since most are unilateral, solitary, and quiescent; hemorrhage and renal compromise are rare. For large (>4 cm), symptomatic or growing AMLs >3 cm, treatment strategies should be similar to those in patients with tuberous sclerosis complex (TSC) [138]. mTOR inhibitor therapy is now the first line approach and is approved for treatment of AMLs in patients with TSC. Embolization, radiofrequency ablation, or nephron-sparing partial nephrectomy are considered for tumors that fail to adequately shrink on mTOR inhibitor therapy or those that are at very high risk of bleeding [138]. Nephron sparing approaches are preferred, and nephrectomy should only be considered as a last resort or when renal cancer is documented or strongly suspected. Further details are provided separately. (See "Renal manifestations of tuberous sclerosis complex".)
Hepatic AMLs generally do not require specific treatment [139-141].
COVID-19 — Individuals with LAM who have coronavirus disease 2019 (COVID-19) should be managed similarly to other patients with chronic lung disease. (See "COVID-19: Management of adults with acute illness in the outpatient setting" and "COVID-19: Management in hospitalized adults".)
Notably, nirmatrelvir-ritonavir can raise the sirolimus blood levels. We ask LAM patients to either hold sirolimus or take sirolimus on alternate days (eg, patients with severe disease) for the duration of treatment (five days).
In a retrospective study, the risk of death after COVID-19 infection in women with LAM was found to be similar to the general population and the use of mTOR inhibitors was not associated with worse outcomes. This study included 91 patients with LAM (mostly sporadic LAM), with 31 percent requiring hospital admission, 2.2 percent requiring noninvasive ventilation, and 2.2 percent requiring mechanical ventilation [142]. Only one patient died, a 59 year old with severe lung disease. Diffusing capacity, but not mTOR inhibitor therapy, was predictive of the need for hospitalization or supplemental oxygen (odds ratio 0.96, 95% CI 0.93-0.99). The young age of this population may explain the favorable outcomes compared with other chronic lung disease cohorts.
Others — Other complications of LAM should be managed similarly to the general population:
●Meningiomas (see "Management of known or presumed benign (WHO grade 1) meningioma" and "Management of atypical and malignant (WHO grade 2 and 3) meningioma")
●Osteoporosis (see "Overview of the management of low bone mass and osteoporosis in postmenopausal women" and "Evaluation and treatment of premenopausal osteoporosis")
●Pulmonary hypertension [143,144] (see "Pulmonary hypertension due to lung disease and/or hypoxemia (group 3 pulmonary hypertension): Treatment and prognosis")
●Pulmonary vascular shunts [145] (see "Therapeutic approach to adult patients with pulmonary arteriovenous malformations")
THERAPY OF UNCLEAR BENEFIT
Statins, doxycycline, hormone manipulation, hydroxychloroquine, celecoxib, resveratrol
●Statins – Statins have potential noncardiovascular benefits, including preclinical evidence suggesting potential for inducing LAM cell death when used in combination with sirolimus. A retrospective review of combined sirolimus and simvastatin therapy showed that the addition of a statin neither enhances nor diminishes the beneficial effects of sirolimus therapy in LAM [146]. A phase II open-label clinical trial where simvastatin was administered in escalating doses to 10 patients with LAM on a stable dose of sirolimus showed that while the combination of simvastatin and sirolimus was safe, there was a trend towards increased FEV1 decline with this combination [86].
●Doxycycline – Doxycycline, a matrix metalloproteinase inhibitor, has been tested as a possible treatment for pulmonary LAM [84,147-150]. Although there is a paucity of data, most studies suggest no benefit. In a trial of 23 women with pulmonary LAM who were randomly assigned to take oral doxycycline 100 mg daily for three months followed by 200 mg daily for 21 months, or matched placebo [84], there was no indication that doxycycline had an effect on mean decline in forced expiratory volume in one second (FEV1), vital capacity, gas transfer, shuttle walk distance, or quality of life. Unfortunately, only 15 subjects completed two years of treatment, and the study was inadequately powered for definitive conclusions.
●Hormone manipulation – Historically, hormonal manipulation has been used to treat LAM, based upon the presumption that estrogen likely plays a role in the pathogenesis of the disease. However, anti-estrogen approaches are not currently recommended for routine use because pivotal trials have not been done and consistent benefit has not been demonstrated [2]. Large randomized trials will be required to identify subpopulations that may benefit (eg, premenopausal patients with pneumothorax, menstrual cycle variation, or lymphatic involvement).
Consistent with American Thoracic Society/Japanese Respiratory Society (ATS/JRS) LAM Guidelines, hormone manipulation should not be used for routine treatment of LAM [2]. This recommendation is based upon lack of convincing evidence for efficacy of various hormonal manipulations, including progestin therapy (high dose medroxyprogesterone acetate given as intramuscular depot injection or orally), tamoxifen (20 mg/day), oophorectomy, androgen therapy, luteinizing hormone-releasing hormone (LHRH) analogs, aromatase inhibitors, and combinations of such therapies [1,82,151-159]. No trial has shown convincing benefits and many experts believe that the potential harms from undesirable adverse effects (eg, osteoporosis, accelerated cardiovascular disease, mood swings, hirsutism, weight gain, venous thromboembolism) preclude recommending them for routine use.
For patients with progressive disease who do not respond to a mechanistic target of rapamycin (mTOR) inhibitor (eg, sirolimus), enrollment in a clinical trial may be offered or a limited trial of estrogen suppression with gonadotropin-releasing hormone (GnRH) agonists (eg, Lupron) plus or minus aromatase inhibitor therapy may be given, depending on menopausal status [1]. The rationale for this approach is strongest in premenopausal patients, especially in those who have symptoms or disease manifestations that vary with the menstrual cycle [160], but strong evidence to support this practice is lacking.
For those who require hormonal manipulation for non-LAM indications (eg, breast cancer, contraception, dysmenorrhea, catamenial pneumothorax), estrogen-containing medications should be avoided including selective estrogen response modulators with estrogen agonist properties such as tamoxifen. Use of aromatase inhibitors, progestins, or low dose estrogen or progestin-eluting intravaginal or intrauterine devices (IUDs) are not contraindicated. Selecting a method of contraception is discussed separately. (See 'Pregnancy and birth control' above.)
●Hydroxychloroquine – Autophagy inhibition has been proposed as a mechanism to induce LAM cell death. Hydroxychloroquine is a potent inhibitor of autophagy and based on promising preclinical evidence was the subject of investigation in a phase I trial in LAM [83]. In this study, 13 LAM patients received hydroxychloroquine in an escalating dose manner along with sirolimus for 24 weeks followed by 24 weeks of observation off treatment. Five subjects withdrew early due to FEV1 decline or adverse effects. Although there was a slight trend towards improved lung function with the combination, the study was not powered to determine efficacy. The role of hydroxychloroquine in the treatment of LAM remains undefined and warrants further investigation.
●Celecoxib – Celecoxib, a selective COX-2 inhibitor, was studied in a phase I open-label trial in 12 patients with LAM not on sirolimus. Celecoxib 200 mg was given daily for 24 weeks. Three participants withdrew due to adverse effects. While the study demonstrated the overall safety of using celecoxib in LAM, larger trials are needed to demonstrate the efficacy of this approach [85].
●Resveratrol – The safety and efficacy of combined resveratrol and sirolimus was assessed in a phase 2 open-label clinical trial involving 25 patients with LAM [87]. Resveratrol was started at a dose of 250 mg daily and titrated to a maximum dose of 500 mg twice daily. The addition of resveratrol was safe and well tolerated and was associated with modest reduction in serum VEGF-D levels and improvement in health-related quality of life. Larger placebo controlled trials are needed to definitively assess the efficacy of resveratrol in LAM.
PROGNOSIS
Lung function decline (off therapy) — Based upon early observational data from national registries and referral centers, the annual decline in forced expiratory volume in one second (FEV1) in untreated LAM patients has been reported to range from 40 to 120 mL/year and higher [157,158,161-163]. Rapid deterioration in lung function can occur at the outset or during the course of the disease [154,158,164]. As an example, in randomized studies of doxycycline and sirolimus, the annual decline in the placebo groups was 90 and 134 mL/year, respectively; although, these studies excluded patients with normal or mildly impaired lung function [47,84]. An analysis of the National Heart, Lung, and Blood Institute's (NHLBI) LAM Registry has demonstrated an annual rate of decline in FEV1 of 89 mL/year, with a faster rate of decline in patients with higher cyst profusion on chest CT scans and in premenopausal as compared with postmenopausal women [163]. The effect of sirolimus on lung function is described separately. (See 'Sirolimus (first line)' above.)
Mortality — While early retrospective studies reported that the median survival for patients with LAM was 8 to 10 years from diagnosis [164,165], data now suggest that survival is longer than previously thought [157,166-171]; these differences likely reflect biases introduced by different modes of data ascertainment (hospital based versus population based cohorts) rather than a true improvement in survival.
●In a population-based registry of 1149 self-identified LAM patients, the estimated median transplant-free survival time in the United States is 29 years from symptom onset and 23 years from diagnosis [166].
●Another study that used data derived from a United Kingdom database reported 10-year survival was 91 percent from onset of symptoms. A wide variation in survival was reported, but 20 percent of the cohort remained alive after 20 years [168].
●In the NHLBI longitudinal LAM registry, the estimated 5-, 10-, 15-, and 20-year transplant-free survival rates were 95, 85, 75, and 64 percent, respectively [163].
Sirolimus may also reduce the time to transplant. A four-year prospective observational study reported that the decline in FEV1 for patients with LAM was slower than previously reported, which may reflect improved therapies for this disease in the sirolimus era [167]. One retrospective study reported an eight-year cumulative survival rate of 90 percent in patients treated with sirolimus compared with 78 percent in those not taking sirolimus despite worse baseline lung function and symptoms in the sirolimus treatment group (eg, FEV1 64 versus 86 percent) [60].
Prognostic factors — While many prognostic factors have been proposed, none have been validated prospectively. These include:
●Clinical factors
•Premenopausal status – Longitudinal studies, case series, and randomized trial data report that premenopausal women tend to have a faster rate of decline in lung function than postmenopausal women [47,154,158,163]. As an example, the NHLBI Longitudinal Study reported that the rate of FEV1 decline was greater in premenopausal subjects (118 mL/year) compared with postmenopausal subjects (74mL/year) and that premenopausal status at baseline was associated with higher rates of death or need for transplant. This finding was supported by a post-hoc analysis of the MILES trial in which premenopausal women with LAM had a FEV1 decline rate that was roughly fivefold higher than the postmenopausal women (approximately 200 mL/year versus approximately 40 mL/year) [45].
•Presentation with dyspnea – Some case series report that presentation with dyspnea on exertion, as opposed to pneumothorax, is associated with a worse prognosis [115,166]. This is intuitively plausible, because a sentinel pneumothorax may reveal LAM in early stages, while dyspnea on exertion at presentation is likely associated with a significant disease.
•Sporadic variant – It is generally thought that women with tuberous sclerosis complex (TSC) have milder lung impairment and a more indolent course than those with sporadic LAM [25]. However, when patients with TSC and sporadic variants with similar degrees of lung function impairment are compared, there is no difference in the rate of lung function decline [172]. The NHLBI Longitudinal Study reported that LAM subtype (TSC-LAM versus sporadic LAM) at baseline was not associated with a poor outcome (death or transplant). Ascertainment bias likely plays a significant role in the perception that TSC-LAM is milder than sporadic LAM since the ability to screen a susceptible TSC population more readily identifies disease at early stages. (See "Tuberous sclerosis complex associated lymphangioleiomyomatosis in adults".)
•Hormonal manipulation – Treatment with hormonal therapy, in particular progesterone, was found in one retrospective study to be associated with an increased risk of death [166]. In another retrospective study, progesterone therapy was found to be associated with an accelerated rate of decline in diffusing capacity for carbon monoxide (DLCO) [154]. In both cases, interpretation was likely confounded by indication, since the group of patients on progesterone was likely more severely affected; prompting the intervention.
●Lung function
•Poor baseline lung function – Several studies report that abnormal pulmonary function on presentation (eg, reduced FEV1 ≤70 percent predicted, elevated total lung capacity [TLC] and a reduced FEV1/forced vital capacity [FVC] ratio) were negative prognostic indicators [154,162,165]. Abnormal gas exchange requiring oxygen supplementation was found to be associated with poor outcome in another study [166] (see "Tuberous sclerosis complex associated lymphangioleiomyomatosis in adults"). The NHLBI LAM Registry Longitudinal Study reported that better baseline lung function (FEV1) was associated with better outcome (eg, death or transplant) [163].
•Reversible airflow obstruction – Observational studies report that reversible airflow obstruction may be a predictor of worse disease severity and disease progression [7,173]. However, airflow obstruction at baseline did not have an impact on outcome (eg, death or transplant) in the NHLBI LAM Registry Longitudinal Study [163].
•Historical rate of lung function decline – Several studies suggest that the best predictor of the future rate of lung function decline is the historical rate of lung function decline. (See 'Monitored observation' above and 'Lung function decline (off therapy)' above.)
●Radiologic findings – Several radiologic and pathologic studies report that predominance of cystic lung disease, rather than ground glass or nodular opacities, is associated with a worse prognosis [7,165,171]. It is unknown whether these patterns represent two distinct histopathologic categories of disease or different stages in disease evolution [165]. A close correlation has also been noted between the extent of the cystic parenchymal changes (as measured by quantitative CT) and disease severity (as determined by spirometry, diffusing capacity, lung volumes, or exercise performance) and rate of decline of lung function [163,174-176].
●High levels of serum vascular endothelial growth factor-D (VEGF-D) – High VEGF-D levels correlate with oxygen supplementation, bronchodilator response, and disease severity in LAM [43], yet the prognostic value of VEGF-D remains uncertain. One observational study involving patients receiving sirolimus showed increased survival in those with baseline VEGF-D of <2000 pg/mL compared with VEGF-D of ≥2000 pg/mL (95 versus 83 percent) [60]. In a separate observational study of LAM patients not on sirolimus, those with serum VEGF-D level ≥800 pg/mL had a significantly greater lung function decline compared with patients with a VEGF-D level <800 pg/mL [44]. However, baseline VEGF-D levels were not predictive of future progression to death or lung transplantation in the NHLBI LAM Registry Longitudinal Study and a separate longitudinal natural history study in Japan [75,163].
Treatment response has also been linked to VEGF-D levels. In a post-hoc analysis of a randomized trial of sirolimus, patients who experienced more than a 42 percent reduction in VEGF-D levels were more likely to exhibit a positive lung function response compared with those whose VEGF-D levels did not respond (<42 percent reduction) [43,45]. VEGF-D responders were also more likely to have elevated baseline VEGF-D levels, possibly due to the use of a percent reduction to define VEGF-D response.
Conversely, it is generally believed that good prognostic features include older age, postmenopausal status, initial presentation with pneumothorax, and normal or mild dysfunction on pulmonary function tests.
ADDITIONAL RESOURCES — The LAM Foundation endorses LAM specialty clinics across the United States and around the world; a list of these clinics, international LAM patient advocacy groups, and other useful information can be found at these sites: The LAM Foundation, the Tuberous Sclerosis Alliance, and the University of Cincinnati.
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Lymphangioleiomyomatosis".)
INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.
Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)
●Basics topics (see "Patient education: Lymphangioleiomyomatosis (The Basics)")
PATIENT PERSPECTIVE TOPIC — Patient perspectives are provided for selected disorders to help clinicians better understand the patient experience and patient concerns. These narratives may offer insights into patient values and preferences not included in other UpToDate topics. (See "Patient perspective: Lymphangioleiomyomatosis (LAM)".)
SUMMARY AND RECOMMENDATIONS
●Terminology – Lymphangioleiomyomatosis (LAM) is a rare multisystem disorder that mostly afflicts women and primarily affects the lung. The term sporadic LAM is used for patients with pulmonary LAM who do not have tuberous sclerosis complex. (See "Sporadic lymphangioleiomyomatosis: Epidemiology and pathogenesis", section on 'Introduction'.)
●General measures – General measures used to treat LAM include reassurance, use of supplemental oxygen, bronchodilators, pulmonary rehabilitation, interventions to manage complications, and avoidance of estrogen-containing medications. The strategic use of the mechanistic target of rapamycin (mTOR) inhibitor, sirolimus, slows progression of respiratory impairment but is not curative. Early referral to or consultation with a LAM center is prudent to establish shared care between LAM experts and local pulmonologists. (See 'General measures' above and 'Treatment of complications' above.)
●Management of lung disease – Our approach is the following:
•Normal or mildly impaired lung function – For most patients with LAM who have normal or mildly impaired lung function defined as a forced expiratory volume in one second (FEV1) ≥70 percent, we suggest monitored observation with frequent postbronchodilator lung function assessments at three month intervals rather than treatment with sirolimus (Grade 2C). Sirolimus may be appropriate in patients with FEV1 in the normal range if lung function is rapidly declining (eg, >100 mL/year) or there are other lung function abnormalities suggestive of a significant burden of LAM in the lung, such as evidence of air trapping (residual volume >120 percent), heavy burden of cysts, abnormal diffusion capacity for carbon monoxide (<lower limit of normal), or >4 percent oxygen desaturation with ambulation. (See 'Normal or mildly impaired lung function' above.)
•Moderate to severe lung impairment – For most patients with sporadic LAM who have moderate to severe lung impairment, as defined by an FEV1 <70 percent predicted, we recommend treatment with sirolimus rather than observation (Grade 1B). In select patients, a short period of observation may be prudent to assess disease progression before initiating sirolimus (eg, postmenopausal women with good pulmonary reserve, given slower rate of progression in that subgroup). Sirolimus is typically administered at 1 to 2 mg orally per day and adjusted to levels required to stabilize lung function and minimize adverse effects ensuring that the trough level does not exceed 10 ng/mL. While the optimal duration of therapy is unknown, we generally continue sirolimus indefinitely, as tolerated. Everolimus is an alternative mTOR inhibitor for those who do not tolerate or respond to sirolimus. (See 'Moderate to severe lung function impairment' above.)
•Refractory disease – For patients who have progressive lung disease despite sirolimus, options include increasing the dose of sirolimus toward the upper end of the therapeutic range (ie, 10 to 15 ng/mL), a trial of replacement with everolimus, participation in clinical trials, and referral for lung transplantation. Although not routinely recommended, hormonal manipulation is sometimes administered in this population. Choosing among these options is dependent upon factors including menopausal status, presence of menstrual cycle associated variation in respiratory symptoms, patient preference and pulmonary reserve. (See 'Refractory disease' above.)
●Treatment of complications – Our approach to complications is the following:
•Pneumothorax – For most patients with LAM and a pneumothorax, after chest tube drainage, we recommend ipsilateral pleurodesis at the time of the initial pneumothorax, rather than waiting for a recurrent event (Grade 1C). We favor mechanical pleurodesis via a video-assisted thoracoscopy and reserve talc pleurodesis for those who fail this approach. Sirolimus should be held in the perioperative period. (See 'Pneumothorax' above.)
•Chylous disease and lymphangioleiomyomas – For most patients with symptomatic chylous accumulations or lymphangioleiomyomas, we suggest treatment with sirolimus rather than other therapies or invasive procedures (Grade 2C). (See 'Chylothorax and chylous ascites' above.)
•Angiomyolipomas – Many renal angiomyolipomas (AMLs) in patients with sporadic LAM do not require therapy since most are unilateral, solitary, and quiescent; hemorrhage and renal compromise are rare. Indications for treatment are described separately. (See 'Angiomyolipomas' above and "Renal manifestations of tuberous sclerosis complex".)
●Investigational agents – Several other agents are under investigation (eg, statins, resveratrol; Clinicaltrials.gov) or have been studied in the past and found to be of no or unclear benefit (eg, doxycycline). Hormonal manipulation has not been shown to be effective for treatment of LAM and should not be used routinely to treat LAM. (See 'Clinical trials' above and 'Therapy of unclear benefit' above.)
●Prognosis – The estimated median transplant-free survival time for pulmonary LAM is 29 years from symptom onset and 23 years from diagnosis. Factors associated with poor prognosis are often those that are associated with faster rates of decline in lung function. Newer data suggests that sirolimus reduces mortality and time to transplant. (See 'Prognosis' above.)
●Educational information – Important educational information is provided at the following sites: The LAM Foundation and the Tuberous Sclerosis Alliance. (See 'Additional resources' above.)
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