Lymphangioleiomyomatosis
Encyclopedia
Lymphangioleiomyomatosis (LAM) is a rare lung disease that results in a proliferation of disorderly smooth muscle
growth (leiomyoma
) throughout the lungs, in the bronchioles, alveolar septa
, perivascular spaces, and lymphatics, resulting in the obstruction of small airways (leading to pulmonary cyst formation and pneumothorax
) and lymphatics
(leading to chylous
pleural effusion
). LAM occurs in a sporadic form, which only affects females, who are usually of childbearing age. LAM also occurs in patients who have tuberous sclerosis
.
The proliferating smooth muscle that occurs in the type of LAM seen in patients with tuberous sclerosis
(TSC-LAM) has been shown to represent clones of the smooth muscle in those patients' renal angiomyolipoma
s. Thus it is believed to represent metastases of this "benign" tumor. There is a female preponderance to TSC-LAM.
AM occurs almost exclusively in women. The average age at onset of symptoms is approximately 34 years (5–7). The first symptoms of the disease can occur before an abnormality is detectable with chest plain radiographs or pulmonary function tests; even when such abnormalities exist, the disease may be initially misdiagnosed. There is often a delay between the onset of symptoms and correct diagnosis.
LAM commonly manifests as exertional dyspnea and recurrent pneumothorax. During the course of the illness, there may be nonproductive cough, hemoptysis, chylous pleural effusion, or chylous ascites. Obstruction of pulmonary venules causes vascular congestion and hemoptysis, and lymphatic obstruction leads to chylothorax and chylous ascites.
The clinical course of patients with LAM shows considerable variation. The disease is believed to be slowly progressive, leading to respiratory failure and death. The 10-year survival from the start of symptoms in a study at our institution was 49% (7), although reported figures range from an 8.5-year survival probability of 38% to a 10-year survival of 79% (8). Differences in survival rates may be due to improvements in diagnosis, particularly regarding the contribution of high-resolution CT, and do not mean that the progression of the disease has changed substantially. Diagnosis of mild asymptomatic forms may also have contributed to the longer survival rates.
Spirometry studies in LAM patients demonstrate chronic airway obstruction with increased lung volume and decreased CO2 diffusion. The radiologic finding of an interstitial pattern with these spirometric results in a young woman narrows the differential diagnosis to some forms of emphysema, Langerhans cell histiocytosis, and sarcoidosis. The information provided by HRCT is essential for differentiating LAM from these conditions.
Numerous therapeutic strategies have been described to treat LAM. In light of the reports of clinical worsening of the disease during pregnancy and with use of exogenous estrogens, many clinicians have applied therapeutic hormone manipulation. Antiestrogen therapy, first used in the early 1980s, consists of surgical castration by oophorectomy or administration of tamoxifen, progesterone, and gonadotropin-releasing hormone agonist or luteinizing hormone–releasing hormone. Several studies have reported beneficial effects of antiestrogen hormone therapies for LAM, but careful scrutiny of some of these studies reveals that the treatment improved the chylothorax or chylous ascites, whereas pulmonary involvement seemed to remain stationary or to progress. Since lung transplantation has become available for patients with poor response to therapies, certain treatments must be used with caution. In fact, castration does not clearly demonstrate a beneficial effect on the course of the disease, and the long-term effects of castration, particularly in the postoperative period of lung transplantation, can increase bone complications.
In most cases, chylothorax should be managed conservatively. Chylothorax usually appears early in the course of the disease, when the patient’s functional status is good. Early application of surgical techniques such as pleural abrasion, pleurodesis, or pleurectomy must be avoided because these treatments might limit future lung transplantation. Medical treatment includes tamoxifen, progesterone, and, in some cases, a low-fat diet.
When the patient’s functional status declines, bilateral lung transplantation is the best therapeutic option. The guidelines indicating transplantation include progression despite medical treatment, forced expiratory volume in 1 second (FEV1)/forced vital capacity ratio of less than 50%, total lung capacity of greater than 130%, and FEV1 of less than 30%. In the largest published series of lung transplantations in LAM patients, the average FEV1 at the time of evaluation for the procedure was 24%.
Common postoperative complications of lung transplantation are bacterial, viral, and fungal infections; acute rejection episodes; and chronic rejection. Complications specific to LAM are pneumothorax of the native lung after single-lung transplantation, chylothorax, recurrence of LAM, and abdominal complications
LAM commonly manifests as exertional dyspnea and recurrent pneumothorax. During the course of the illness, there may be nonproductive cough, hemoptysis, chylous pleural effusion, or chylous ascites. Obstruction of pulmonary venules causes vascular congestion and hemoptysis, and lymphatic obstruction leads to chylothorax and chylous ascites.
The clinical course of patients with LAM shows considerable variation. The disease is believed to be slowly progressive, leading to respiratory failure and death. The 10-year survival from the start of symptoms in a study at our institution was 49% (7), although reported figures range from an 8.5-year survival probability of 38% to a 10-year survival of 79% (8). Differences in survival rates may be due to improvements in diagnosis, particularly regarding the contribution of high-resolution CT, and do not mean that the progression of the disease has changed substantially. Diagnosis of mild asymptomatic forms may also have contributed to the longer survival rates.
Spirometry studies in LAM patients demonstrate chronic airway obstruction with increased lung volume and decreased CO2 diffusion. The radiologic finding of an interstitial pattern with these spirometric results in a young woman narrows the differential diagnosis to some forms of emphysema, Langerhans cell histiocytosis, and sarcoidosis. The information provided by HRCT is essential for differentiating LAM from these conditions.
Vascular endothelial growth factor D is elevated in the serum of patients with LAM. In patients with typical cystic changes on high resolution CT scanning serum levels of greater than 800 pg/ml are considered to be diagnostic for LAM.
A lung biopsy may be necessary to make diagnosis in some patients. Video-assisted thoracoscopic biopsy is the most definitive and widely used technique, but transbronchial biopsy can also be effective In some cases, the diagnosis of LAM can be made with confidence on clinical grounds (without biopsy) in patients with typical cystic changes on high resolution CT scanning of the lung and findings of tuberous sclerosis, angiomyolipoma or chylothorax
Numerous therapeutic strategies have been described to treat LAM. In light of the reports of clinical worsening of the disease during pregnancy and with use of exogenous estrogens, many clinicians have applied therapeutic hormone manipulation. Antiestrogen therapy, first used in the early 1980s, consists of surgical castration by oophorectomy or administration of tamoxifen, progesterone, and gonadotropin-releasing hormone agonist or luteinizing hormone–releasing hormone. Several studies have reported beneficial effects of antiestrogen hormone therapies for LAM, but careful scrutiny of some of these studies reveals that the treatment improved the chylothorax or chylous ascites, whereas pulmonary involvement seemed to remain stationary or to progress. Since lung transplantation has become available for patients with poor response to therapies, certain treatments must be used with caution. In fact, castration does not clearly demonstrate a beneficial effect on the course of the disease, and the long-term effects of castration, particularly in the postoperative period of lung transplantation, can increase bone complications.
In most cases, chylothorax should be managed conservatively. Chylothorax usually appears early in the course of the disease, when the patient’s functional status is good. Early application of surgical techniques such as pleural abrasion, pleurodesis, or pleurectomy must be avoided because these treatments might limit future lung transplantation. Medical treatment includes tamoxifen, progesterone, and, in some cases, a low-fat diet.
When the patient’s functional status declines, bilateral lung transplantation is the best therapeutic option. The guidelines indicating transplantation include progression despite medical treatment, forced expiratory volume in 1 second (FEV1)/forced vital capacity ratio of less than 50%, total lung capacity of greater than 130%, and FEV1 of less than 30%. In the largest published series of lung transplantations in LAM patients, the average FEV1 at the time of evaluation for the procedure was 24%.
Common postoperative complications of lung transplantation are bacterial, viral, and fungal infections; acute rejection episodes; and chronic rejection. Complications specific to LAM are pneumothorax of the native lung after single-lung transplantation, chylothorax, recurrence of LAM, and abdominal complications (9).
None of these therapies has been shown to be clearly efficacious, and all have undesirable side-effects. There is some evidence which shows that tamoxifen may actually cause worsening of LAM in some patients.
When pulmonary function deteriorates to the point where oxygenation is inadequate, lung transplantation may be considered. Following lung transplant, LAM patients have Kaplan-Meier estimator
s (survival curves) similar to other lung transplant patients. Although LAM has been reported to recur in the transplanted lung http://ats.ctsnetjournals.org/cgi/content/full/87/1/e6, there have been no reported cases of graft failure or death due to recurrence..
A single case report of an apparent response to Doxycycline
has recently been reported. However, this therapy has not been proven in a clinical trial.
Sirolimus
has recently been tested for the treatment of LAM. The MILES Trial (Multicenter International LAM Efficacy of Sirolimus Trial) was a randomized, double-blind, and placebo-controlled. The primary endpoint was the rate of change in lung function over one year on treatment. A total of 89 patients were enrolled at 13 sites in the United States, Japan and Canada. To be eligible, patients had to have definite LAM and abnormal lung function. In general, patients who enrolled had moderately severe LAM with lung function of about 50% of predicted. Patients were treated with sirolimus or placebo for one year and followed off drug for one year. The data demonstrated that sirolimus stabilized lung function, improved some measures of quality of life and functional performance, and reduced serum VEGF-D in patients with LAM. Side effects were more frequent in the sirolimus group, but serious adverse events were balanced between the groups. The benefit of sirolimus waned when the drug was stopped, and lung function decline resumed. The conclusion of the study was that sirolimus can be considered for treatment of moderately severe LAM. Additional studies are needed to determine the risks and benefits of treatment in patients with milder disease and those who take the drug for longer than 1 year.
Smooth muscle
Smooth muscle is an involuntary non-striated muscle. It is divided into two sub-groups; the single-unit and multiunit smooth muscle. Within single-unit smooth muscle tissues, the autonomic nervous system innervates a single cell within a sheet or bundle and the action potential is propagated by...
growth (leiomyoma
Leiomyoma
A leiomyoma is a benign smooth muscle neoplasm that is not premalignant. They can occur in any organ, but the most common forms occur in the uterus, small bowel and the esophagus.- Etymology:* Greek:** λεῖος leios "smooth"...
) throughout the lungs, in the bronchioles, alveolar septa
Septum
In anatomy, a septum is a wall, dividing a cavity or structure into smaller ones.-In human anatomy:...
, perivascular spaces, and lymphatics, resulting in the obstruction of small airways (leading to pulmonary cyst formation and pneumothorax
Pneumothorax
Pneumothorax is a collection of air or gas in the pleural cavity of the chest between the lung and the chest wall. It may occur spontaneously in people without chronic lung conditions as well as in those with lung disease , and many pneumothoraces occur after physical trauma to the chest, blast...
) and lymphatics
Lymphatic system
The lymphoid system is the part of the immune system comprising a network of conduits called lymphatic vessels that carry a clear fluid called lymph unidirectionally toward the heart. Lymphoid tissue is found in many organs, particularly the lymph nodes, and in the lymphoid follicles associated...
(leading to chylous
Chyle
Chyle is a milky bodily fluid consisting of lymph and emulsified fats, or free fatty acids . It is formed in the small intestine during digestion of fatty foods, and taken up by lymph vessels specifically known as lacteals...
pleural effusion
Pleural effusion
Pleural effusion is excess fluid that accumulates between the two pleural layers, the fluid-filled space that surrounds the lungs. Excessive amounts of such fluid can impair breathing by limiting the expansion of the lungs during ventilation.-Pathophysiology:...
). LAM occurs in a sporadic form, which only affects females, who are usually of childbearing age. LAM also occurs in patients who have tuberous sclerosis
Tuberous sclerosis
Tuberous sclerosis or tuberous sclerosis complex is a rare multi-system genetic disease that causes non-malignant tumors to grow in the brain and on other vital organs such as the kidneys, heart, eyes, lungs, and skin. A combination of symptoms may include seizures, developmental delay, behavioral...
.
Causes
Sporadic LAM almost always affects women.The proliferating smooth muscle that occurs in the type of LAM seen in patients with tuberous sclerosis
Tuberous sclerosis
Tuberous sclerosis or tuberous sclerosis complex is a rare multi-system genetic disease that causes non-malignant tumors to grow in the brain and on other vital organs such as the kidneys, heart, eyes, lungs, and skin. A combination of symptoms may include seizures, developmental delay, behavioral...
(TSC-LAM) has been shown to represent clones of the smooth muscle in those patients' renal angiomyolipoma
Angiomyolipoma
Angiomyolipoma are the most common benign tumour of the kidney and are composed of blood vessels, smooth muscle cells and fat cells. Angiomyolipoma are strongly associated with the genetic disease tuberous sclerosis, in which most individuals will have several angiomyolipoma affecting both kidneys...
s. Thus it is believed to represent metastases of this "benign" tumor. There is a female preponderance to TSC-LAM.
AM occurs almost exclusively in women. The average age at onset of symptoms is approximately 34 years (5–7). The first symptoms of the disease can occur before an abnormality is detectable with chest plain radiographs or pulmonary function tests; even when such abnormalities exist, the disease may be initially misdiagnosed. There is often a delay between the onset of symptoms and correct diagnosis.
LAM commonly manifests as exertional dyspnea and recurrent pneumothorax. During the course of the illness, there may be nonproductive cough, hemoptysis, chylous pleural effusion, or chylous ascites. Obstruction of pulmonary venules causes vascular congestion and hemoptysis, and lymphatic obstruction leads to chylothorax and chylous ascites.
The clinical course of patients with LAM shows considerable variation. The disease is believed to be slowly progressive, leading to respiratory failure and death. The 10-year survival from the start of symptoms in a study at our institution was 49% (7), although reported figures range from an 8.5-year survival probability of 38% to a 10-year survival of 79% (8). Differences in survival rates may be due to improvements in diagnosis, particularly regarding the contribution of high-resolution CT, and do not mean that the progression of the disease has changed substantially. Diagnosis of mild asymptomatic forms may also have contributed to the longer survival rates.
Spirometry studies in LAM patients demonstrate chronic airway obstruction with increased lung volume and decreased CO2 diffusion. The radiologic finding of an interstitial pattern with these spirometric results in a young woman narrows the differential diagnosis to some forms of emphysema, Langerhans cell histiocytosis, and sarcoidosis. The information provided by HRCT is essential for differentiating LAM from these conditions.
Numerous therapeutic strategies have been described to treat LAM. In light of the reports of clinical worsening of the disease during pregnancy and with use of exogenous estrogens, many clinicians have applied therapeutic hormone manipulation. Antiestrogen therapy, first used in the early 1980s, consists of surgical castration by oophorectomy or administration of tamoxifen, progesterone, and gonadotropin-releasing hormone agonist or luteinizing hormone–releasing hormone. Several studies have reported beneficial effects of antiestrogen hormone therapies for LAM, but careful scrutiny of some of these studies reveals that the treatment improved the chylothorax or chylous ascites, whereas pulmonary involvement seemed to remain stationary or to progress. Since lung transplantation has become available for patients with poor response to therapies, certain treatments must be used with caution. In fact, castration does not clearly demonstrate a beneficial effect on the course of the disease, and the long-term effects of castration, particularly in the postoperative period of lung transplantation, can increase bone complications.
In most cases, chylothorax should be managed conservatively. Chylothorax usually appears early in the course of the disease, when the patient’s functional status is good. Early application of surgical techniques such as pleural abrasion, pleurodesis, or pleurectomy must be avoided because these treatments might limit future lung transplantation. Medical treatment includes tamoxifen, progesterone, and, in some cases, a low-fat diet.
When the patient’s functional status declines, bilateral lung transplantation is the best therapeutic option. The guidelines indicating transplantation include progression despite medical treatment, forced expiratory volume in 1 second (FEV1)/forced vital capacity ratio of less than 50%, total lung capacity of greater than 130%, and FEV1 of less than 30%. In the largest published series of lung transplantations in LAM patients, the average FEV1 at the time of evaluation for the procedure was 24%.
Common postoperative complications of lung transplantation are bacterial, viral, and fungal infections; acute rejection episodes; and chronic rejection. Complications specific to LAM are pneumothorax of the native lung after single-lung transplantation, chylothorax, recurrence of LAM, and abdominal complications
Clinical Features
LAM occurs almost exclusively in women. The average age at onset of symptoms is approximately 34 years (5–7). The first symptoms of the disease can occur before an abnormality is detectable with chest plain radiographs or pulmonary function tests; even when such abnormalities exist, the disease may be initially misdiagnosed. There is often a delay between the onset of symptoms and correct diagnosis.LAM commonly manifests as exertional dyspnea and recurrent pneumothorax. During the course of the illness, there may be nonproductive cough, hemoptysis, chylous pleural effusion, or chylous ascites. Obstruction of pulmonary venules causes vascular congestion and hemoptysis, and lymphatic obstruction leads to chylothorax and chylous ascites.
The clinical course of patients with LAM shows considerable variation. The disease is believed to be slowly progressive, leading to respiratory failure and death. The 10-year survival from the start of symptoms in a study at our institution was 49% (7), although reported figures range from an 8.5-year survival probability of 38% to a 10-year survival of 79% (8). Differences in survival rates may be due to improvements in diagnosis, particularly regarding the contribution of high-resolution CT, and do not mean that the progression of the disease has changed substantially. Diagnosis of mild asymptomatic forms may also have contributed to the longer survival rates.
Spirometry studies in LAM patients demonstrate chronic airway obstruction with increased lung volume and decreased CO2 diffusion. The radiologic finding of an interstitial pattern with these spirometric results in a young woman narrows the differential diagnosis to some forms of emphysema, Langerhans cell histiocytosis, and sarcoidosis. The information provided by HRCT is essential for differentiating LAM from these conditions.
Vascular endothelial growth factor D is elevated in the serum of patients with LAM. In patients with typical cystic changes on high resolution CT scanning serum levels of greater than 800 pg/ml are considered to be diagnostic for LAM.
A lung biopsy may be necessary to make diagnosis in some patients. Video-assisted thoracoscopic biopsy is the most definitive and widely used technique, but transbronchial biopsy can also be effective In some cases, the diagnosis of LAM can be made with confidence on clinical grounds (without biopsy) in patients with typical cystic changes on high resolution CT scanning of the lung and findings of tuberous sclerosis, angiomyolipoma or chylothorax
Numerous therapeutic strategies have been described to treat LAM. In light of the reports of clinical worsening of the disease during pregnancy and with use of exogenous estrogens, many clinicians have applied therapeutic hormone manipulation. Antiestrogen therapy, first used in the early 1980s, consists of surgical castration by oophorectomy or administration of tamoxifen, progesterone, and gonadotropin-releasing hormone agonist or luteinizing hormone–releasing hormone. Several studies have reported beneficial effects of antiestrogen hormone therapies for LAM, but careful scrutiny of some of these studies reveals that the treatment improved the chylothorax or chylous ascites, whereas pulmonary involvement seemed to remain stationary or to progress. Since lung transplantation has become available for patients with poor response to therapies, certain treatments must be used with caution. In fact, castration does not clearly demonstrate a beneficial effect on the course of the disease, and the long-term effects of castration, particularly in the postoperative period of lung transplantation, can increase bone complications.
In most cases, chylothorax should be managed conservatively. Chylothorax usually appears early in the course of the disease, when the patient’s functional status is good. Early application of surgical techniques such as pleural abrasion, pleurodesis, or pleurectomy must be avoided because these treatments might limit future lung transplantation. Medical treatment includes tamoxifen, progesterone, and, in some cases, a low-fat diet.
When the patient’s functional status declines, bilateral lung transplantation is the best therapeutic option. The guidelines indicating transplantation include progression despite medical treatment, forced expiratory volume in 1 second (FEV1)/forced vital capacity ratio of less than 50%, total lung capacity of greater than 130%, and FEV1 of less than 30%. In the largest published series of lung transplantations in LAM patients, the average FEV1 at the time of evaluation for the procedure was 24%.
Common postoperative complications of lung transplantation are bacterial, viral, and fungal infections; acute rejection episodes; and chronic rejection. Complications specific to LAM are pneumothorax of the native lung after single-lung transplantation, chylothorax, recurrence of LAM, and abdominal complications (9).
Prognosis
Exact data on survival rates are difficult to collect because LAM is often misdiagnosed as asthma or other more common diseases, and may not be correctly identified until it is in an advanced condition. A comprehensive study of all known British LAM patients found that out of 21 patients that had been observed for 15 years or more since diagnosis, 18 were still alive; and 11 of 12 patients that had been observed for 20 years or more were alive, however, no data is available on respiratory disability.Complications
- Worsening pulmonary insufficiency
- PneumothoraxPneumothoraxPneumothorax is a collection of air or gas in the pleural cavity of the chest between the lung and the chest wall. It may occur spontaneously in people without chronic lung conditions as well as in those with lung disease , and many pneumothoraces occur after physical trauma to the chest, blast...
, secondary to rupture of a cyst into the pleural space - ChylousChyleChyle is a milky bodily fluid consisting of lymph and emulsified fats, or free fatty acids . It is formed in the small intestine during digestion of fatty foods, and taken up by lymph vessels specifically known as lacteals...
pleural effusionPleural effusionPleural effusion is excess fluid that accumulates between the two pleural layers, the fluid-filled space that surrounds the lungs. Excessive amounts of such fluid can impair breathing by limiting the expansion of the lungs during ventilation.-Pathophysiology:...
s
Treatment
The association of LAM with women of childbearing age suggests that hormonal stimulation plays a role in the disease process, and several approaches to treatment involve diminishing the effect of estrogen. At one time or another, therapeutic approaches have included- progesteroneProgesteroneProgesterone also known as P4 is a C-21 steroid hormone involved in the female menstrual cycle, pregnancy and embryogenesis of humans and other species...
- oophorectomyOophorectomyOophorectomy is the surgical removal of an ovary or ovaries. The surgery is also called ovariectomy, but this term has been traditionally used in basic science research describing the surgical removal of ovaries in laboratory animals...
- tamoxifenTamoxifenTamoxifen is an antagonist of the estrogen receptor in breast tissue via its active metabolite, hydroxytamoxifen. In other tissues such as the endometrium, it behaves as an agonist, hence tamoxifen may be characterized as a mixed agonist/antagonist...
- gonadotropin-releasing hormoneGonadotropin-releasing hormoneGonadotropin-releasing hormone , also known as Luteinizing-hormone-releasing hormone and luliberin, is a tropic peptide hormone responsible for the release of follicle-stimulating hormone and luteinizing hormone from the anterior pituitary. GnRH is synthesized and released from neurons within...
(GnRH) agonists - androgenAndrogenAndrogen, also called androgenic hormone or testoid, is the generic term for any natural or synthetic compound, usually a steroid hormone, that stimulates or controls the development and maintenance of male characteristics in vertebrates by binding to androgen receptors...
therapy
None of these therapies has been shown to be clearly efficacious, and all have undesirable side-effects. There is some evidence which shows that tamoxifen may actually cause worsening of LAM in some patients.
When pulmonary function deteriorates to the point where oxygenation is inadequate, lung transplantation may be considered. Following lung transplant, LAM patients have Kaplan-Meier estimator
Kaplan-Meier estimator
The Kaplan–Meier estimator, also known as the product limit estimator, is an estimator for estimating the survival function from life-time data. In medical research, it is often used to measure the fraction of patients living for a certain amount of time after treatment. In economics, it can be...
s (survival curves) similar to other lung transplant patients. Although LAM has been reported to recur in the transplanted lung http://ats.ctsnetjournals.org/cgi/content/full/87/1/e6, there have been no reported cases of graft failure or death due to recurrence..
A single case report of an apparent response to Doxycycline
Doxycycline
Doxycycline INN is a member of the tetracycline antibiotics group, and is commonly used to treat a variety of infections. Doxycycline is a semisynthetic tetracycline invented and clinically developed in the early 1960s by Pfizer Inc. and marketed under the brand name Vibramycin. Vibramycin...
has recently been reported. However, this therapy has not been proven in a clinical trial.
Sirolimus
Sirolimus
Sirolimus , also known as rapamycin, is an immunosuppressant drug used to prevent rejection in organ transplantation; it is especially useful in kidney transplants. A macrolide, sirolimus was first discovered as a product of the bacterium Streptomyces hygroscopicus in a soil sample from Easter...
has recently been tested for the treatment of LAM. The MILES Trial (Multicenter International LAM Efficacy of Sirolimus Trial) was a randomized, double-blind, and placebo-controlled. The primary endpoint was the rate of change in lung function over one year on treatment. A total of 89 patients were enrolled at 13 sites in the United States, Japan and Canada. To be eligible, patients had to have definite LAM and abnormal lung function. In general, patients who enrolled had moderately severe LAM with lung function of about 50% of predicted. Patients were treated with sirolimus or placebo for one year and followed off drug for one year. The data demonstrated that sirolimus stabilized lung function, improved some measures of quality of life and functional performance, and reduced serum VEGF-D in patients with LAM. Side effects were more frequent in the sirolimus group, but serious adverse events were balanced between the groups. The benefit of sirolimus waned when the drug was stopped, and lung function decline resumed. The conclusion of the study was that sirolimus can be considered for treatment of moderately severe LAM. Additional studies are needed to determine the risks and benefits of treatment in patients with milder disease and those who take the drug for longer than 1 year.