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.