What is the management and treatment of cystic pulmonary diseases, such as Lymphangioleiomyomatosis (LAM) and Pulmonary Langerhans Cell Histiocytosis (PLCH), in patients with respiratory symptoms and impaired lung function?

Management and Treatment of Cystic Pulmonary Diseases

Lymphangioleiomyomatosis (LAM)

Pharmacological Treatment

For LAM patients with FEV1 <70% predicted or declining lung function, sirolimus is the standard of care and should be initiated rather than observation. 1, 2 This represents a fundamental shift from experimental therapy to evidence-based treatment, with goals to stabilize lung function, improve functional performance, and enhance quality of life. 1, 2

Sirolimus dosing and monitoring:

• Target serum trough levels of 5-15 ng/mL, though emerging evidence suggests low-dose sirolimus (trough <5 ng/mL) may also be effective 1, 2
• Common adverse effects include mucositis, diarrhea, nausea, hypercholesterolemia, acneiform rash, lower extremity swelling, ovarian cyst formation, dysmenorrhea, proteinuria, drug-induced pneumonitis, and increased infection risk due to immunosuppression 2

For symptomatic chylous fluid accumulations (pleural effusions or ascites), sirolimus should be initiated before invasive management such as percutaneous drainage or indwelling drainage devices. 1, 2 However, chylous effusions may require several months to respond to mTOR inhibitors and can recur after treatment cessation. 1, 2 Consider fat-free diet with medium-chain triglyceride supplementation as adjunctive therapy. 2

Therapies NOT Recommended

Doxycycline should NOT be used for LAM treatment, as no beneficial effects on respiratory impairment have been confirmed despite its theoretical mechanism of inhibiting matrix metalloproteinases. 1, 2 The recommendation against doxycycline is based on a randomized trial showing no benefit, with potential adverse effects including dyspepsia, photosensitivity, nausea, and diarrhea. 1

Hormonal therapies (progesterone, GnRH agonists, selective estrogen receptor modulators, oophorectomy) are NOT recommended due to lack of proven benefit and inconsistent results across studies. 1, 2 Despite compelling evidence that hormonal factors influence LAM pathogenesis, no hormonal therapeutic approach has demonstrated consistent beneficial outcomes. 1

Disease Monitoring

Disease progression should be evaluated by repeating lung function tests at 3-6 monthly intervals during the first year following diagnosis, then at 3-12 monthly intervals depending on severity and progression. 1 FEV1 and DLCO are the best current indicators of disease progression and survival. 1

For TSC-LAM patients with normal lung function who remain stable after 1 year of observation, regular follow-up by a respiratory specialist may not be required, but respiratory evaluation should be performed if symptoms develop. 1

Diagnostic Approach

VEGF-D testing should be performed before proceeding to diagnostic lung biopsy in patients with characteristic cystic abnormalities on CT but no confirmatory clinical or extrapulmonary features. 1, 2 A serum VEGF-D >800 pg/ml has high specificity for LAM and can eliminate the need for invasive lung biopsy. 1 However, a negative result should not exclude LAM due to the high false-negative rate. 1

HRCT is the investigation of choice for detecting LAM, with characteristic features including multiple (>10) thin-walled round well-defined air-filled cysts with preserved or increased lung volume. 1

Lung biopsy does not provide prognostic information and should not be performed for this purpose alone. 1

Screening Recommendations

Females with TSC should undergo screening for LAM by HRCT at age 18 years and if negative, again at age 30-40 years. 1 HRCT should be repeated if persistent respiratory symptoms develop. 1

All patients with LAM or suspected LAM should have abdomino-pelvic CT at diagnosis to identify angiomyolipomas and other abdominal lesions. 1

Management of Complications

All LAM patients must be warned of the risk of pneumothorax (occurs in ~40% at presentation and 66% during disease course, with ~75% recurrence rate after first episode) and instructed to seek urgent medical attention for pneumothorax symptoms. 1 Pneumothorax management requires joint care by chest physician and thoracic surgeon, with chemical pleurodesis and surgical procedures as needed. 2

Patients considering pregnancy must be informed of greater risk of pneumothorax and chylous effusion during pregnancy, with possible acceleration of lung function decline. 1 Those with recurrent pneumothorax outside pregnancy or poor baseline lung function are at particularly high risk. 1

For renal angiomyolipomas, sirolimus should not be first-line therapy but may be considered on an individual basis for symptomatic angiomyolipomas not amenable to embolization or conservative surgery. 2

General Management

Patients should maintain normal weight and refrain from smoking. 1 History of pleurodesis or pleurectomy is not a contraindication to lung transplantation, though patients must be informed of increased risk of perioperative pleural bleeding. 2

Pulmonary Langerhans Cell Histiocytosis (PLCH)

While the provided evidence focuses primarily on LAM, PLCH is mentioned as a key differential diagnosis characterized by diffuse cystic lung disease. 3, 4, 5 PLCH is strongly associated with smoking, and smoking cessation is the primary intervention. 4 High-resolution CT plays a crucial role in distinguishing PLCH from LAM based on cyst morphology, distribution, and associated radiologic findings. 3, 4

Key Differentiating Features

PLCH typically shows upper and mid-lung zone predominance with sparing of costophrenic angles, whereas LAM shows diffuse distribution. 3, 4 PLCH cysts may be more irregular and associated with nodules, while LAM cysts are uniformly round and thin-walled. 3, 4, 5