Efficacy of sirolimus for the prevention of recurrent pneumothorax in patients with lymphangioleiomyomatosis: a case series

Zhou et al. Orphanet Journal of Rare Diseases (2018) 13:168 https://doi.org/10.1186/s13023-018-0915-2 LETTER TO THE EDITOR Open Access Efficacy of sirolimus for the prevention of recurrent pneumothorax in patients with lymphangioleiomyomatosis: a case series Li Zhou, Ruoyun Ouyang*, Hong Luo, Siying Ren, Ping Chen, Yating Peng, Ting Liu and Guiqian Liu Abstract Pneumothorax is one of the most common symptoms in patients with lymphangioleiomyomatosis (LAM). However, current management strategies for patients with LAM who present with recurrent pneumothorax remain inadequate. Here, we describe the successful prevention of recurrent pneumothorax by sirolimus treatment in five women with LAM. Before sirolimus treatment, all patients had received supplemental oxygen support, repeated chest tube drainage, or surgeries for management of the recurrent pneumothorax. Sirolimus treatment was initiated when the pneumothorax was completely resolved, and no patient developed pneumothorax during treatment. Moreover, they exhibited a significantly improved subjective quality of life, increased exercise capacity, and mild adverse effects such as mucositis, irregular menstruation, and delayed wound healing. On discontinuation of sirolimus or in the event that the plasma sirolimus level was markedly low, pneumothorax tended to relapse. The findings from these cases provide valuable insights that will aid in the improvement of treatment strategies for patients with LAM and recurrent pneumothorax. Keywords: Sirolimus, Lymphangioleiomyomatosis, Pneumothorax, Treatment strategy, Recurrence Introduction Lymphangioleiomyomatosis (LAM) is a rare, progressive, cystic lung disease that mostly affects women of child-bearing age and is characterized by abnormal smooth muscle cell proliferation. LAM is associated with a series of clinical manifestations such as dyspnea, recurrent pneumothorax, hemoptysis, chylous effusion, renal angiomyolipoma (AML), retroperitoneal masses, and respiratory failure [1]. Pneumothorax is a common manifestation of LAM. Previous studies have demonstrated that approximately 66% of patients with LAM may exhibit pneumothorax; importantly, 70% of these patients may experience recurrent ipsilateral or contralateral pneumothoraces [2, 3]. However, management strategies for recurrent spontaneous pneumothorax in patients with LAM remain controversial and inadequate. Sirolimus, a common mammalian target of rapamycin (mTOR) inhibitor, is considered the first effective drug for patients with LAM. According to the guidelines * Correspondence: Department of Pulmonary and Critical Care Medicine, The Second Xiangya Hospital, Central South University, 139 Renmin Road, Changsha, China published in 2016 [4], sirolimus is recommended for the following types of patients with LAM: patients with moderately impaired lung function [a forced expiratory volume in 1 s (FEV1) of less than 70% predicted] or progressively declining lung function (decline rate for FEV1, over 90 ml/year) and patients with chylous effusion. However, to date, sirolimus has not been recommended for patients with LAM presenting with pneumothorax. Here, we describe the clinical course of five women with LAM who presented with recurrent pneumothorax that was successfully prevented by sirolimus treatment. We also discuss the effectiveness of sirolimus therapy and other therapeutic options for the prevention of pneumothorax recurrence in patients with LAM, in an attempt to promote the development of better treatment strategies for this patient population. Case series Case 1 A 33-year-old female nonsmoker with a 4-month history of intermittent chest pain and dyspnea at rest, which © The Author(s). 2018 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Zhou et al. Orphanet Journal of Rare Diseases (2018) 13:168 recurred every 2 weeks, was admitted to our hospital at 31 weeks of gestation. Four months ago, she had been admitted after experiencing these symptoms for the first time. A chest radiograph at that time revealed left hydropneumothorax with 90% lung compression. The patient received closed chest tube drainage (CTD). However, left pneumothorax recurred during rest or minimal activity in the 20th, 25th, 28th, and 30th weeks of gestation. For every recurrent episode, she was admitted to a local hospital, where she received CTD and was discharged only after radiographic confirmation that the pneumothorax had completely resolved. At the current admission, arterial blood gas analysis indicated type I respiratory failure with a partial pressure of oxygen (PaO2) of 51 mmHg. The patient was treated with supplemental oxygen and continuous CTD. Between the 31st and 32nd weeks of gestation, abdominal ultrasound revealed that the umbilical cord was twisted around the neck of the fetus. At 33rd weeks, the patient underwent a cesarean section and successfully delivered a baby with a low birth weight of 1720 g and normal Apgar scores. High-resolution computed tomography (HRCT) revealed small, thin-walled cystic lesions diffused throughout all lung fields. The serum level of vascular endothelial growth factor-D (VEGF-D) was 6608 pg/ml. The patient was diagnosed with LAM, and she began treatment at a dose of 2 mg/day from 28 days after delivery. At 18 months after treatment initiation, the patient’s exercise capacity and quality of life exhibited considerable improvement, and she was able to resume work. She was followed up for 3 years and had not experienced recurrent pneumothorax at the time of writing this report. She could perform all daily activities, including jogging, housekeeping, and routine work. The only sirolimusassociated adverse effect was mucositis, which gradually ameliorated and resolved with time during the course of sirolimus treatment. A follow-up pulmonary function test (PFT) revealed a forced vital capacity (FVC) of 2.20 l (75.3% predicted), FEV1 of 1.85 l (66.3% predicted), and an FEV1/FVC ratio of 84.1% (100% predicted). Moreover, she could cover a distance of 480 m in a 6-min walk test (6MWT). Her baby showed normal growth and remained healthy without breast milk. Case 2 A 23-year-old female nonsmoker was admitted to our hospital with 6 days of dyspnea. The chest radiograph revealed bilateral hydropneumothoraces (50% and 80% compression in the left and right lungs, respectively). Two months ago, a large intraperitoneal mass had been detected during prenatal examination, and (...truncated)