Lymphangioleiomyomatosis in Ireland: estimated prevalence clinical characteristics and disease burden and the value of cyst burden score as a biomarker

Lymphangioleiomyomatosis (LAM) is a low-grade metastasising neoplasm that causes cystic lung disease. It is part of a group of diffuse cystic lung diseases which also includes follicular bronchiolitis (FB), lymphatic interstitial pneumonia (LIP), Birt-Hogg-Dubé syndrome (BHD) and pulmonary Langerhans cel histiocytosis (PLCH), amyloidosis, light chain deposition disease (LDCC), cystic metastases and infections such as pneumocystis jiroveci. It is associated with pulmonary cysts, chylothorax, renal angioleiomyomas (AML), and is found either in patients with tuberous sclerosis complex (TSC) or is sporadic. It impacts women exclusively during their reproductive years. Reported prevalence is 3-8 cases per million women worldwide, which is likely an underestimate. It is postulated that LAM cells, which originate in the uterus, travel through the lymphatics, deposit in the lung tissue and lead to parenchymal destruction and cyst formation. It is purported that the disease process is driven by oestrogen and is worsening with the use of hormonal contraception, hormone replacement therapy (HRT) and pregnancy. Patients with LAM present with cough, shortness of breath and pneumothorax. A portion of patients are diagnosed incidentally. The diagnosis of LAM is based on American/ Japanese and European Respiratory Society guidelines and where characteristic CT plus presence AML, chylothorax, presence of TSC, lymphangioleiomyoma over vascular endothelial growth factor-D (VEGF-D) over 800pg/ml are diagnostic of LAM. VEGF-D is available as a diagnostic and prognostic biomarker. Disease course for patients with LAM is variable from mild disease to progressive lung function decline leading to respiratory failure. Treatment is available in the form of mTOR inhibitors which have been shown to slow decline. Lung function specifically forced expiratory volume over 1 second (FEV1) is used for surveillance of lung function decline, where an FEV1 of less than 70% is an indication for treatment. The aim of this study was to determine the prevalence of LAM in collaboration with colleagues in Northern Europe. We hypothesized that the prevalence has previously been under reported, which we found to be the case. Secondly, the clinical characteristics and disease burden in patients with LAM attending the rare lung disease clinic at St Vincent’s University was described. The results suggested a more rapid decline in lung function as measured by FEV1 than previously reported elsewhere. Details on burden of disease are also provided including the role of VEGF-D as a biomarker of disease within the cohort. This chapter also includes details of efforts to develop VEGF-D testing locally, comparing results from those processed with colleagues in the United States. Finally, in an effort to develop other biomarkers of disease in LAM, chapter 5 describes the value of cyst burden scores (LAV%) in LAM and it correlates with other markers of disease severity. These results adds to the growth literature in the field of this rare disease, as part of the effort to better understand those with this rare disease.