Figure 6: (a) chest X-ray at presentation (b) chest X-ray at discharge (c) spirometry at first visit (only visit)
Following removal of intercostal drainage, her oxygen saturation at room air improved, respiratory rate dropped to normal and she remained afebrile for the last one week preceding her discharge. Her spirometry however showed an FEV1 of 48% of predicted and FVC of 46% of predicted for her BMI, age, sex and ethnicity. Considering the poor initial lung function she was advised to start mTOr inhibitor sirolimus along with simvastatin pending their availability. The patient was also counselled about avoidance of activities that might increase disease activity and/or risk of pneumothorax.
Discussion :
Pulmonary lymphangioleiomyoma or PLAM is a rarely reported diffuse parenchymal lung disease with the recent Indian ILD registry finding it in 0.2% of patients of DPLD2. Previously thought to be a disease exclusive in females of reproductive age group, it is now well-established that few male patients of tuberous sclerosis may have LAM-like lung radiology and even fewer may show characteristic LAM lesions1. PLAM is found in two forms: (1) sporadic form which is extremely rare (4.9 in 1000000 females) and (b) In association with tuberous sclerosis (1 in 6000-12000 live births). Although pathognomonic, the Vogt triad of mental retardation, seizure and adenoma sebaceum is not seen together in more than 30% patients of tuberous sclerosis, and most of the cases are suspected at childhood. It is estimated that a third of patients with tuberous sclerosis may have PLAM. PLAM patients are usually young females of reproductive age group who present with worsening shortness of breath and cough in absence of clinical improvement on bronchodilators and ICS for obstructive airway disease. The pulmonary manifestations include small nodules that ultimately cause airspaces to enlarge as result of proximal obstruction leading to formation of cysts of various size (0.2-2 cm). Cysts often rupture leading to formation of pneumothorax which may prompt the first hospital visit and diagnosis. Chylous pleural effusion and ascites are common associations. Also found are abdominal leiomyomas are renal angiomyolipomas. When associated with tuberous sclerosis, a neurocutaneous syndrome, these patients would show various degrees of mental retardation, history of seizure, cortical tubers and subependymal nodules and/or giant cell astrocyotoma along with cutaneous signs of ashleaf macule, shagren patches, periungual fibromas and adenoma sebaceum.
Studies suggest that a mutation of a tumor suppressor gene TSC2 (with some involvement of TSC1) leads to unopposed cellular signaling in favour of tumorigenesis, inappropriate growth, proliferation and evasion of apoptosis through the mTOR, mTORC1 and mTORC2 (intracellular serine/threonine kinase) activation, which are otherwise kept in check by a complex of tuberin, hamartin and TBC1D7, proteins coded by the healthy TSC2 gene. This leads to excessive proliferation of LAM cells, a group of smooth muscle cells suspected to be of uterine origin, in lung, kidney and abdomen, leading to formation of hamartomatous growths elsewhere and nodules in lung that eventually block small airways causing formation of cysts due to trapping of air. Relative over activity of matrix metalloproteinases in the face of reduce inhibitors (TIMP) also contribute to the damage. A strong association between estrogen and disease activity has been noted repeatedly, but remains to be proven by benefits in clinical trials3.
Although the 2017 ATS guidelines suggest that a lung biopsy is necessary to diagnose the disease if other features of it are not evident, they also recognize the hazards associated with the invasive tests considering poor lung reserve in these patients. Current diagnostic criteria allow establishment of diagnosis in a patient with suggestive clinical profile and radiological evidence (classical characteristic HRCT thorax findings- diffuse thin-walled round cysts with normal intervening lung) in presence of any one of the following: (1) tuberous sclerosis complex (2)abdominal lymphangioleiomyoma (3)Renal angiomyolipoma (4)chylous effusion/ascites (5)serum VEGF-D levels in excess of 800 pg/ml4. As pneumothorax is a common and recurrent complication, pleurodesis is to be offered at the first instance of pneumothorax. Patient should also be cautioned about the poor outcomes of later pregnancies, risks of disease worsening with high estrogen states and risks associated with air travel. Complications like osteoporosis, chylous effusion/ascites and bleeding from angiomyolipomas/lymphangioleiomyomas are to be managed as necessary. ATS has strongly recommended that mTOR-inhibitor sirolimus be used as a first line agent whenever evidence of deteriorating lung function is there (FEV1<70% of predicted) with or without chylothorax or gradually enlarging lymphangioleiomyomas5. It recognized that simvastatin, hydroxychloroquine (autophagy inhibitor), and check-point (PD-1) inhibitors may hold a promising future as therapeutic options6.
Conclusion :
Our patient was diagnosed entirely on the basis of findings of non-invasive modalities, yet in full accordance with the ATS guidelines. Her uniqueness lies in the fact that she showed no hint of any neurological symptoms, she only had the adenoma sebaceum component of the classical Vogt clinical triad and was diagnosed in adulthood while most with this disease is diagnosed at early childhood. This highlights the fact that if high level of clinical suspicion is maintained in investigating the underlying disease process in every case of hydropneumothorax or pneumothorax in a young patient, who apparently do not have the classical risk factors, many cases of so called rare cystic lung diseases may be unveiled at a higher rate. There have been very few cases reported of this disease from India, a fact which has left us with little chance of making any stride in researching more about its management strategies7. As LAM is a treatable disease, this insight might be extremely beneficial for the unfortunate patients of this orphan disease.