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 period3. However, atypical cases with reactive pulmonary
vasculature that overcame the pulmonary hypertension crisis with
pulmonary vasodilators have rarely been reported, as in our case1.
Various pulmonary vasodilators have been used to manage ACD/MPV,
including inhaled nitric oxide (iNO), prostanoids, and phosphodiesterase
(PDE) inhibitors 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 epoprostenol4. 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 effective5. 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 obstruction1.
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 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 inconclusive1,2.
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/MPV1,3. A heterozygous pathogenic variant in the FOXF1
gene was identified in our patient using WES.
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.