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\begin{document}

\title{A little more than just air and fluid: an uncommon disease underlying a
simple hydropneumothorax}



\author[1]{Akash Sengupta}%
\author[2]{Saikat Datta}%
\affil[1]{RG Kar Medical College and Hospital}%
\affil[2]{MJN MEDICAL COLLEGE AND HOSPITAL COOCHBEHAR}%


\vspace{-1em}



  
  \date{May 27, 2024}


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A LITTLE MORE THAN JUST AIR AND FLUID: AN UNCOMMON CASE OF
HYDROPNEUMOTHORAX

Dr. Akash Sengupta\textsuperscript{1}, Dr. Saikat
Dutta\textsuperscript{2}

\textsuperscript{1} senior resident, department of chest
medicine;\textsuperscript{2} Professor and head of the department,
department of medicine, MJN medical college and hospital, Cooch behar,
West Bengal

\textbf{Email:}akashsengupta09@gmail.com (corresponding author)

\textbf{Case report:}

A non-hypertensive, non-diabetic, euthyroid young female of 25 years age
from rural Coochbehar presented to us at MJN Medical College and
Hospital, with 1 year history of mild cough and mMRC grade 1 dyspnea,
with the dyspnea worsening abruptly since last week. It was accompanied
by low grade fever. Her dyspnea was not associated with wheezing,
diurnal, seasonal or postural variation; cough was dry~{and without
diurnal variation. She denied chest pain, joint pain, history of
cyanosis, paroxysmal nocturnal dyspnoea, history of prior tuberculosis,
or any history suggestive of allergy or atopy. She had no addiction, no
exposure to any known agents that might cause hypersensitivity; her
menstrual history was normal and she has one living issue of 16 months
age.}

During examination it was noted that she had a tall stature (height: 170
cm) but no features of joint hyperextensibility, loose, lax skin, eye or
heart problems. Her vitals were all stable except for her respiratory
rate being 30/ minute and pulse rate being 110/minute. Her accessory
muscles of respiration were visibly working.

She had multiple brownish nodular skin lesions localized around her
nasolabial folds and surrounding areas of the face \textbf{(FIG 1.A).}\selectlanguage{english}
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\textbf{Figure 1: A. brownish nodular lesion over nasolabial region; B.
Hypopigmented macule over back}

Further clinical examination revealed mediastinal shift towards left,
right sided hyper resonant percussion notes till right
4\textsuperscript{th} intercostal space and stony dull below, presence
of shifting dullness, and absent breath sounds over right hemithorax-
all suggestive of right sided hydropneumothorax. Abdominal examination,
neurological examination, examination of the genitourinary tract and
other systems did not reveal any significant finding.\selectlanguage{english}
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A chest X-ray was readily performed and established the diagnosis of
right sided hydropneumothorax with mediastinal shift to the left side.
The left lung field showed few non-homogenous opacities and cystic
changes but could not be characterized with certainty \textbf{(FIG 2} ).

\textbf{Figure 2: the initial chest X-ray of the patient showing right
sided hydropneumothorax.}

Although spontaneous hydropneumothorax in a young female of reproductive
age group is not that uncommon, especially in a lean, thinly built, tall
individual, the finding of specific skin lesions in association with the
aforementioned clinical profile raised possibility of some underlying
disease as the cause of the hydropneumothorax.

The prime candidates were lymphangioleiomyomatosis with tuberous
sclerosis (with the skin lesions being that of adenoma sebaceum) and
Birt-Hogg-Dube syndrome (BHD) (skin lesions could be fibrofolliculoma).
The other possibilities included Marfan's syndrome (associated with
hereditary predisposition to pneumothorax and tall, thinly built people
with hyperextensible joints and multiple other deformities), Cutis Laxa,
alpha-1-antitrypsin deficiency along with common differentials of
hydropneumothorax such as bronchopleural fistula due to infective
causes, secondary infection of a primary spontaneous pneumothorax etc.
The latter ones had little clinical evidence to gain any support as
plausible diagnoses.

Even among the first two, LAM associated with TSC was far more likely
than the others. But tuberous sclerosis patients usually show a spectrum
of mental retardation, gives some history of seizure or other
neurological symptoms, none of which was found in this patient despite
meticulous history taking.

On closer examination, the patient also had hypopigmented macules on her
back \textbf{(FIG 1:B)} , and confetti-like patches of hypopigmented
lesions scattered over her back and extremities.

Patient's dyspnea was managed with insertion of an intercostal drain in
her right 4\textsuperscript{th} intercostal space at the midaxillary
line and over time her right lung gradually re-expanded. Her pleural
fluid analysis showed characters of an exudate rich in mixed
inflammatory cells predominantly lymphocytes (55\%) with an ADA value of
7 mg/dl. Lipid analysis of the fluid revealed that the triglyceride
levels was 39 mg/dl. Pap smear and Malignant cell block did not reveal
any evidence of malignancy.

In the meantime, further investigations were planned including a
contrast enhanced CT scan of the thorax along with a thin slice
high-resolution CT thorax, MRI brain, CT abdomen and echocardiography.
Spirometry with bronchodilator reversibility test was delayed until the
full expansion of the right lung.. A dermatologist's opinion was sought
along with that of a neurologist and radiologist in interpreting the
clinico-radiological spectrum of the patient from their perspectives.\selectlanguage{english}
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\textbf{Figure 3: HRCT thorax of the patient}\selectlanguage{english}
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The CT thorax revealed that, in addition to the now resolving
hydropneumothorax with the intercostal drain in-situ, the lung
parenchyma was riddled with multiple randomly distributed thin-walled
round cysts of various sizes, but predominantly small (\textless{}2cm).
The intervening lung was predominantly normal. A few fibrotic bands and
resolving consolidation as evidence of prior infection were also seen.
The findings were highly suggestive of pulmonary
lymphangioleiomyomatosisin this clinical context \textbf{(FIG 3).} MRI
brain revealed multiple cortical tubers and subependymal signal-intense
white matter nodules strongly suggestive of tuberus sclerosis

\textbf{(FIG 4).}

\textbf{Figure 4: MRI brain of the patient}

The CE abdomen identified large renal angiomyolipomas encircling both
the kidneys \textbf{(FIG 5).} The dermatologist opined that the skin
changes are that of adenoma sebaceum and ashleaf macules, consistent
with cutaneous signs of tuberus sclerosis. The pleural fluid
bacteriology and NAAT reports virtually excluded infection as the
primary cause of the hydropneumothorax.\selectlanguage{english}
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\textbf{Figure 5: renal angiomyolipoma (stars) found on CT scan of
abdomen}

Taking all these into account, in accordance with the diagnostic
criteria laid down by the American Thoracic Society, the patient was
diagnosed as a case of pulmonary lymphangioleiomyomatosis associated
with tuberus sclerosis complex (TSC-LAM).

After her right lung fully expanded, the sonological examination and
X-rays both showed an automatic pleural thickening probably induced by
prior infection and the presence of the intercostal drainage tube.
Additional chemically induced pleurodesis was therefore deemed
unnecessary (\textbf{figure 6} ).

\textbf{Hosted file}

\verb`image9.emf`  available at \url{https://authorea.com/users/669429/articles/669886-a-little-more-than-just-air-and-fluid-an-uncommon-disease-underlying-a-simple-hydropneumothorax}\selectlanguage{english}
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\textbf{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.

\textbf{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 DPLD\textsuperscript{2}. 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
lesions\textsuperscript{1}. 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 trials\textsuperscript{3}.

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/ml\textsuperscript{4}. 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\textless{}70\% of predicted) with or without chylothorax or
gradually enlarging lymphangioleiomyomas\textsuperscript{5}. It
recognized that simvastatin, hydroxychloroquine (autophagy inhibitor),
and check-point (PD-1) inhibitors may hold a promising future as
therapeutic options\textsuperscript{6}.

\textbf{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 strategies\textsuperscript{7}. As LAM is a treatable disease,
this insight might be extremely beneficial for the unfortunate patients
of this orphan disease.

\textbf{INFORMED CONSENT:}

Written informed consent was obtained from the patient to publish this
report in accordance with the journal's patient consent policy.

\textbf{CONSENT STATEMENT:}

(TRANSLATED FROM BENGALI: THE MOTHER TONGUE OF THE PATIENT)

I, after being adequately informed about the extent and objectives of
the article in consideration, give my full consent in sane mind and
without any undue force, regarding using my clinical data and relevant
images for the sake of advancing medical research and education
activities.

Sd

Kamana Barman

\textbf{References} :

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  New York: McGraw-Hill education; 2023. P-1015. AND 6. P-1019-1023.
\item
  Singh S, Collins BF, Sharma BB, Joshi JM, Talwar D, Katiyar S, et al.
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\item
  Kristof A S, Moss J, Pulmonary lymphangioleiyomyomatosis. In:
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  Fishman's pulmonary diseases and disorders. 6\textsuperscript{th} ed.
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\end{enumerate}\selectlanguage{english}
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Gupta N, Finlay GA, Kotloff RM, Strange C, Wilson KC, Young LR, et al.
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management. An official American thoracic society/Japanese respiratory
society clinical practice guideline. Am J Respir Crit Care Med
{[}Internet{]}. 2017;196(10):1337--48.\strut
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\bottomrule
\end{longtable}

McCormack FX, Gupta N, Finlay GR, et al. Official American Thoracic
Society/Japanese Respiratory Society Clinical Practice Guidelines:
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Koul PA, Mehfooz N. Sirolimus in lymphangioleiomyomatosis: A case in
point for research in `orphan' diseases. Lung India 2019;36:353-5

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