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.