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\begin{document}

\title{Atypical presentation and management of a neonate with alveolar
capillary dysplasia: A case report}



\author[1]{Niki Dermitzaki}%
\author[1]{Chatzigiannis N}%
\author[1]{Maria Baltogianni}%
\author[1]{Kamperi ME}%
\author[2]{Vlahos A}%
\author[2]{Makis A}%
\author[3]{Konstantinos Douros}%
\author[1]{Vasileios Giapros}%
\affil[1]{Neonatal Intensive Care Unit, University of Ioannina, Greece}%
\affil[2]{Pediatric Department, University of Ioannina, Greece}%
\affil[3]{Respiratory Unit, Third Department of Pediatrics, Athens University Medical School, Greece}%


\vspace{-1em}



  
  \date{May 26, 2024}


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\textbf{Atypical presentation and management of a neonate with alveolar
capillary dysplasia: A case report}

To the Editor,

Alveolar capillary dysplasia with misalignment of capillary veins
(ACD/MCV) is a rare interstitial lung disease caused by maldevelopment
of alveoli and capillaries. Neonates typically present with intractable
pulmonary hypertension within the first 48 hours of life and have a very
short life expectancy \textsuperscript{1}. However, atypical cases have
been described with a late, less fulminant clinical presentation and
prolonged survival on pulmonary vasodilators, providing a window for
bilateral lung transplantation \textsuperscript{2}.

\textbf{Case presentation}

Our patient is a female neonate born at 37 weeks of gestation, weighing
3080 gr after an uncomplicated pregnancy. She was admitted to the
neonatal intensive care unit (NICU) at the age of two hours due to
pneumothorax, which was managed conservatively and absorbed. On the
second day of life, she was intubated due to worsening respiratory
distress. Over the next several days, unsuccessful extubation trials
were attempted. Eventually, she was weaned off oxygen on the 11th day.
However, on postnatal day 16, significant respiratory deterioration was
noted. Echocardiography revealed moderate pulmonary hypertension, and
sildenafil and dopamine were initiated. The patient's clinical condition
and echocardiography findings gradually deteriorated. High-frequency
oscillatory ventilation (HFOV) was commenced with a fraction of inspired
oxygen (fiO2) up to 1.0. As our patient continued to deteriorate
(maximum oxygenation index OI:32 on day 23), we used intravenous
iloprost as a pulmonary vasodilator, titrated up to 20 ng/kg/min in
combination with levosimendan up to 0.1 mcg/kg/min, to improve cardiac
contractility and reduce afterload and pulmonary resistance. Of note,
nitric oxide was unavailable in our center at this time. Although
gradual improvement in pulmonary hypertension was noticed, our patient
developed severe pulmonary edema, which was managed with a continuous
intravenous infusion of furosemide titrated up to 0.4mg/kg/h.
Intravenous medications were gradually withdrawn, and we could switch to
conventional ventilation on the day of life 34. The infant was extubated
ten days later.

Computed tomography of the lungs showed bilateral symmetrical
ground-glass opacification, and genetic testing with whole exome
sequencing (WES) revealed a heterozygous missense variant of the FOXF1
gene (c.229T\textgreater{}C;p.Phe77Leu) in exon 1.

Our patient remained stable on a high-flow nasal cannula (HFNC) until
the 68th day when she was reintubated, and echocardiography revealed
severe pulmonary hypertension. On the 72nd day of life, she was
transferred to another NICU at the request of her parents. She remained
intubated, treatment with pulmonary vasodilators was continued, and
finally, a tracheostomy was performed. She eventually died at five
months of age. The parents have consent to report the medical details of
the neonate.

\textbf{Discussion}

ACD/MPV is a rare and almost universally lethal condition caused by an
abnormal development of the pulmonary blood vessels. The clinical
picture of ACD/MVP resembles that of persistent pulmonary hypertension
of the newborn (PPHN), and the initial therapeutic approach is similar.
The response to pulmonary vasodilators is not sustained in typical
cases, and despite escalating care, patients die in the neonatal
period\textsuperscript{3}. However, atypical cases with reactive
pulmonary vasculature that overcame the pulmonary hypertension crisis
with pulmonary vasodilators have rarely been reported, as in our
case\textsuperscript{1}.

Various pulmonary vasodilators have been used to manage ACD/MPV,
including inhaled nitric oxide (iNO), prostanoids, and phosphodiesterase
(PDE) inhibitors \textsuperscript{3}. Our center was not equipped with
iNO, so we initially used PDE inhibitors. However, our patient
progressively deteriorated. Eventually, she showed gradual improvement
with high-dose intravenous iloprost and levosimendan.

The potential usefulness of prostacyclins in ACD/MPV cases has been
described. It has been previously reported that these patients may
benefit from higher-than-usual doses of intravenous
epoprostenol\textsuperscript{4}. We used intravenous iloprost, a
synthetic analogue of PGI2, titrated up to 20ng/kg/min, well above the
usual neonatal range, without significant adverse effects.

There is limited data regarding the use of levosimendan in neonates,
mostly in cardiac surgery patients. A few case series have reported its
use in neonates with heart failure and pulmonary hypertension without
structural heart disease, concluding that it is safe and
effective\textsuperscript{5}. Our patient showed marked improvement with
no side effects.

Despite improvement in pulmonary hypertension, our patient developed
severe pulmonary edema, requiring continuous infusion of furosemide.
This complication of pulmonary vasodilators in infants with ACD/MPV has
been previously described and reinforces the diagnosis. It is probably
due to combined capillary and post-capillary
obstruction\textsuperscript{1}.

Histopathological examination is considered the gold standard for
diagnosis. Characteristic histopathological features of the lung tissue
include significantly reduced and misplaced alveolar capillaries, medial
hypertrophy of the small pulmonary arteries, and misplaced pulmonary
veins \textsuperscript{2,3}. Although it has been proposed that atypical
cases may be associated with an uneven distribution of disease and areas
of normal lung parenchyma, the evidence is still
inconclusive\textsuperscript{1,2}.

Genetic testing may obviate the need for a biopsy, which is not always
feasible in critically ill patients. However, a negative result does not
preclude the diagnosis. The FOXF1 gene, which encodes a transcription
factor crucial for the lung and other organs' mesenchymal development,
was found to be involved in the pathogenesis of
AVD/MPV\textsuperscript{1,3}. A heterozygous pathogenic variant in the
FOXF1 gene was identified in our patient using WES.

\textbf{Conclusion}

ACD/MPV should be suspected in any infant presenting with severe
hypoxemia and pulmonary hypertension without an apparent causative
factor. As there is no curative treatment, managing these patients is
challenging. However, some infants, as our patient, may benefit from
pulmonary vasodilators to overcome pulmonary hypertension crisis, thus
providing a time window for life-saving lung transplants. Inhaled nitric
oxide, the only FDA-approved drug for neonatal pulmonary hypertension,
can be used in patients with ACD/MPV, although it is not always
effective and not universally available due to the high cost of
equipment. Therefore, it is crucial to identify alternative agents that
are both safe and effective for use in neonates. In our case, due to the
unavailability of iNO, we had to use alternative off-label pulmonary
vasodilators for neonatal use and dosages beyond the usual neonatal
range. Our patient's pulmonary hypertension crisis was successfully
resolved by levosimendan and high-dose intravenous iloprost without any
adverse effects. These drugs may provide a therapeutic option for
pulmonary hypertension in patients with ADV/MPV when iNO is ineffective
or unavailable.

\textbf{References}

1. Edwards JJ, Murali C, Pogoriler J, Frank DB, Handler SS, Deardorff
MA, Hopper RK. Histopathologic and Genetic Features of Alveolar
Capillary Dysplasia with Atypical Late Presentation and Prolonged
Survival. J Pediatr. 2019 Jul;210:214-219

2. Alturkustani M, Li D, Byers JT, Szymanski L, Parham DM, Shi W, Wang
LL. Histopathologic features of alveolar capillary dysplasia with
misalignment of pulmonary veins with atypical clinical presentation.
Cardiovasc Pathol. 2021 Jan-Feb;50:107289.

3. Slot E, Edel G, Cutz E, van Heijst A, Post M, Schnater M, Wijnen R,
Tibboel D, Rottier R, de Klein A. Alveolar capillary dysplasia with
misalignment of the pulmonary veins: clinical, histological, and genetic
aspects. Pulm Circ. 2018 Jul-Sep;8(3):2045894018795143.

4. Fukasawa Y, Yamamoto H, Ito M, Saito A, Go K, Morimoto Y, Yasuda K,
Sato Y, Hayakawa M, Kato T. Case report: High-dose epoprostenol therapy
in pediatric patients with pulmonary hypertension and developmental lung
disease. Front Pediatr. 2023 Mar 3;11:1116434.

5. Schroeder L, Holcher S, Leyens J, Geipel A, Strizek B, Dresbach T,
Mueller A, Kipfmueller F. Evaluation of levosimendan as treatment option
in a large case-series of preterm infants with cardiac dysfunction and
pulmonary hypertension. Eur J Pediatr. 2023 Jul;182(7):3165-3174.

\textbf{Authors}

Dermitzaki N\textsuperscript{1}, Chatzigiannis N\textsuperscript{1},
Baltogianni M\textsuperscript{1}, Kamberi ME\textsuperscript{1}, Vlahos
A\textsuperscript{2}, Makis A\textsuperscript{2}, Douros
K\textsuperscript{3}, Giapros V\textsuperscript{1}

\textbf{Affiliations}

1 Neonatal Intensive Care Unit, School of Medicine, University of
Ioannina, Ioannina, Greece

2 Department of Pediatrics, School of Medicine, University of Ioannina,
Ioannina, Greece 3 Respiratory Unit, Third Department of Pediatrics,
Athens University Medical School, ''Attikon'' University Hospital,
Haidari, Greece

\textbf{Funding} : This research received no external funding.

\textbf{Conflicts of Interest:} The authors declare no conflicts of
interest.

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