Alveolar Capillary Dysplasia

Historical Perspective

MacMahon made the first mention of “congenital alveolar dysplasia of the lungs” in 1947, when he described a condition “involving both lungs uniformly or only a portion of a single lobe” associated with abnormalities in other organs (7).

The seminal case reported by Janney and colleagues in 1981 (8) described a term neonate who developed severe respiratory distress 12 hours after birth and a clinical course consistent with persistent fetal circulation. Despite the best treatment available at the time, the infant developed severe bradycardia and hypotension and died at 40 hours of life. Post mortem examination of the lungs showed “failure of formation and ingrowth of alveolar capillaries”, abnormal air–blood barriers, and anomalous veins in the bronchovascular bundles. Janney and her team designated this entity of persistent fetal circulation with abnormalities of pulmonary vascular development “congenital alveolar capillary dysplasia.”

Since these early descriptions, more than 100 cases of ACD/MPV have been reported worldwide. Most of them have been sporadic, de novo events, but approximately 10% involved siblings, suggesting a heritable form of the disease (9–11). For several reasons, these case reports almost certainly underestimate the true prevalence of ACD/MPV. First, the definitive diagnosis of ACD/MPV currently depends on histological examination of lung tissue on autopsy or ante mortem lung biopsy, and neither of these diagnostic modalities is universally pursued in the setting of a critically ill or dying newborn (12). Second, many infants born with ACD/MPV have associated malformations in other organ systems that may allow the lung pathology to go undetected. Third, the diagnosis may be missed by pathologists unfamiliar with the disorder (13–16). Last, evidence is mounting to suggest that a less severe phenotype compatible with prolonged survival might exist, although definitive diagnostic criteria for this group are yet to be established (17–19).

Epidemiology

The incidence or prevalence of ACD/MPV is not yet known, but there are clearly more cases than those that have been reported formally in the literature. Furthermore, it seems likely that some cases originally classified as idiopathic persistent pulmonary hypertension of the newborn (PPHN) may actually have been ACD/MPV (14, 20). A slight male predominance (60%) has appeared in reported cases (21, 22). No geographic pattern is apparent; cases have been distributed worldwide.

More than 90% of affected infants are born at term (17, 21), and in greater than 60% of cases, onset of cyanosis and respiratory failure occurs within 48 hours of birth (9, 23). In a recent review of 21 cases of ACD/MPV from England, Melly and colleagues (24) proposed that the severity of disruption in capillary density and lack of contact with the alveolar epithelium may be two major factors that determine clinical course and prognosis, and they ascribed the potential for survival beyond the neonatal period in a minority of patients to higher capillary density and apposition. The prevalence of this milder, potentially survivable phenotype is not known.

The number of infants with ACD/MPV treated with extracorporeal life support is unknown, but several case series cite infants with unexplained PPHN who fail to improve with full cardiopulmonary support (15, 25). Twenty-two percent of neonates referred for PPHN do not survive, according to 2010 Extracorporeal Life Support Organization registry data (26). Given the decrease in extracorporeal membrane oxygenation (ECMO) referrals for PPHN (27, 28) and the generally favorable outcomes, this group of nonsurvivors may include infants with ACD/MPV.

Pathogenesis

The pathogenesis of both ACD/MPV and its associated pulmonary hypertension remain to be fully explained. Cullinane and colleagues (13) were the first to suggest that the primary pulmonary vascular anomaly is a failure of fetal lung vascularization in response to an unknown teratogen. With the number of pulmonary capillaries drastically reduced, blood entering an individual lung unit can only drain via anomalous (“misaligned”) veins. The obstruction that is created leads to the occlusive changes observed in the pulmonary arterial circulation. Sirkin and colleagues (29) shared the view that an early antenatal insult leads to a deficient pulmonary capillary bed and a decreased bronchial generation count, and suggested a genetic defect could explain both the extrapulmonary findings and ACD/MPV occurrence in families. Others have proposed that the muscular thickening in the small pulmonary arteries may be the primary lesion, resulting from pulmonary vasoconstriction, with consequent failure of normal alveolar capillary development (30). However, this latter theory does not adequately explain the vascular changes observed in utero, because gas exchange does not involve the alveolar capillary interface before birth. Further identification of the genetic mechanisms involved in the pathogenesis of ACD/MPV will likely clarify the underlying defect in pulmonary vascular development that results in irreversible hypoxemia and pulmonary hypertension and explain the characteristic patterns of functional response to therapy.

Pathophysiology and Diagnosis

Genetics: Past and Future Approaches

The genetic etiology of ACD/MPV has remained elusive for decades (46). Pedigree analyses of ACD/MPV patients' families have suggested both autosomal dominant and recessive patterns of inheritance (10), thus implicating at least two causative genes.

Treatment

The clinical approach to infants with ACD/MPV is no different than that for other neonates presenting with PPHN. However, the response to therapy is often minimal and/or not sustained, which may serve as an initial diagnostic clue.

Because the hypoxemia is so severe and unrelenting, many practitioners will attempt lung recruitment strategies, such as high-frequency ventilation or surfactant. However, infants with ACD/MPV usually present with minimal parenchymal lung disease. Lung recruitment strategies may induce respiratory alkalosis and a transient improvement in oxygenation, but may also contribute to rapid deterioration due to lung overdistension and associated compromise of right atrial filling. Recent case series have reported high rates of unilateral or bilateral pneumothorax, which could be another consequence of excessive airway pressures (20, 54).

Most infants with ACD/MPV will develop progressive hypotension due to right ventricular failure and/or refractory hypoxemia. Because the hypoxemia and pulmonary hypertension cannot be effectively reversed, cardiotonic agents have only a minimal or transient effect in infants with ACD/MPV.

Although transient responses to pulmonary vasodilator therapy can be observed in infants with ACD/MPV, no infant has been reported to have a sustained response to any available pulmonary vasodilator. In a study of five infants with documented ACD/MPV, all responded to inhaled nitric oxide with improved oxygenation (>200 mm Hg) and reduced pulmonary artery pressures, but deterioration and death followed within hours (25). Other reports have demonstrated a similar pattern of response to inhaled or intravenous prostacyclin (55, 56), suggesting that the pattern of initial improvement followed by deterioration may be specific to the anomalous vasculature of ACD/MPV. To date, there are no reports of sildenafil use in infants with ACD/MPV.

ECMO is used at some point in the clinical course in most case series of ACD/MPV, and a report from the U.K. ECMO experience found that ACD/MPV was diagnosed in 14% of babies who died after ECMO support. This was almost certainly an underestimate, as ACD/MPV was documented in 33% of babies who had full autopsy examinations (12). At least one additional report showed that ACD/MPV was found in the majority of infants with idiopathic PPHN who did not respond to ECMO (six of seven infants) (20). The registry maintained by the Extracorporeal Life Support Organization indicates that more than 20% of infants with idiopathic PPHN do not respond to ECMO support, which should prompt investigation for ACD/MPV (20, 57).

Because none of the supportive therapies described above has changed the expected mortality due to ACD/MPV, lung transplantation is currently the only option that might prolong survival. Although successful lung transplantation in infants with ACD/MPV has not been reported, achieving early diagnosis by lung biopsy is an essential first step, followed by strategies that sufficiently prolong survival. A recent report demonstrated survival of an infant for more than 3 months after presentation in the neonatal period (58), indicating that lung transplantation may provide effective treatment for carefully selected affected infants.

Late Presenters and Long-Term Survivors

Reports of infants presenting with clinical features of ACD/MPV beyond the neonatal period have begun to emerge. Thus far, four reports of infants presenting with fulminant disease at 5 weeks, 7 weeks, 12 weeks, and 7 months have been published (4, 18, 19, 59). Although two of them presented with symptoms serious enough to warrant brief periods of respiratory observation in a neonatal intensive care unit before discharge (4, 59), the remaining two appeared asymptomatic and were discharged home as well babies (18, 19). With such limited information, it is difficult to estimate the number of patients with delayed presentation of ACD/MPV, but it is certainly greater than the four mentioned above. Until more specific diagnostic tools become available, similarities in lung pathology and clinical findings should increase diagnosis using the same approach to lung tissue sampling in late presenters as for those who present early.

The pathophysiology underlying the development of ACD/MPV has yet to be fully characterized, and mechanisms that might explain delayed presentation are even less clear. How infants with structural defects at the level of the air–blood barrier can remain virtually asymptomatic for weeks or months is one of the urgent questions now under investigation. The findings of Melly and colleagues (24) suggest that variations in disease severity and timing of presentation correspond to alterations in capillary density and contact with the alveolar epithelium. Better lobular development and patchy involvement have also been cited to explain the delay in onset of symptoms (9, 30, 60), but this remains controversial. In fact, thus far, the histological appearance of lung tissue taken from early and late presenters has been strikingly similar (4). As such, mechanistic explanations for delayed presentation of ACD/MPV will require the identification of triggers for the acute deterioration that signals the onset of fulminant disease. One of the most plausible explanations suggests that the onset of symptoms, whether early or delayed, results from vasoconstriction of a hypertrophied arterial bed (30), which then triggers a pulmonary hypertensive crisis. Interestingly, viral upper respiratory infections, known to trigger pulmonary hypertension in those at risk, were reported in two of the late presenters. Regardless, the remarkable overlap in clinical course and outcome of infants with advanced disease, whether the onset is early or delayed, requires further investigation.

There appears to be no survival advantage in presenting late. Once symptoms develop, the infant with delayed presentation of ACD/MPV experiences the same downward spiral that results in death.

A better understanding of the genetic and physiologic mechanisms that govern the ACD/MPV phenotype and timing of presentation may lead to expanding the current case definition to include long-term survivors. Of note, a recent case report in the British Journal of Radiology (61) described a 21-year-old woman with newly diagnosed pulmonary hypertension and “misplaced pulmonary arteries” located in the interlobular septae (in addition to ones that were located normally in the bronchovascular bundles). Although disputed, the authors claim that the histological findings are similar to those described in newborns with PPHN and may represent a forme fruste of the vascular anomaly seen in ACD/MPV. If replicated, their findings would lend support to the hypothesis that milder, survivable forms of the disorder exist.

Future Directions

Advances in ACD/MPV genetics research, combined with support from federal health-related research agencies, such as the Centers for Disease Control and Prevention and the National Institutes of Health, are providing an impetus for ongoing investigation into several aspects of this rare disease. Steadfast commitment by researchers and rare disease coalitions, academic research networks such as the Children's Interstitial Lung Disease Research Network (chILDRN), parent advocacy groups, and others, along with encouraging developments in the areas of genetic technology (i.e., the availability of oligonucleotide comparative genomic hybridization and exome sequencing) and electronic database development (with the impending launch of a state-of-the-art interactive international electronic database for rare lung diseases in children) should accelerate the rate at which further progress will be made.

With this foundation, future activities should place emphasis on the following goals:

1. To identify additional genes or genetic mechanisms operating at the FOXF1 locus involved in the pathogenesis of ACD/MPV, which may elucidate complex phenotype–genotype relationships;

2. To define regulatory mechanisms that determine phenotype, disease severity, timing of presentation, natural history, and outcomes;

3. To refine existing animal models of ACD/MPV (49, 62) for the purposes of developing prenatal and postnatal diagnostic tests and exploring new approaches to treatment;

4. To increase awareness and disseminate information about ACD/MPV across a broad spectrum of health-care providers;

5. Through the above activities, to identify a greater number of cases that can generate reliable and valid data for the purposes of developing accurate diagnostic criteria and preferred treatment practices.

It is through the accomplishment of the above goals that ACD/MPV may transform from a uniformly lethal disorder into one that is treatable and/or preventable.

Summary

ACD/MPV is a rare, lethal, neonatal developmental lung disorder that results in abnormal alveolar air–blood barriers for gas exchange, severe hypoxemia, and pulmonary hypertension. It may be distinguished from idiopathic PPHN by an incomplete response to interventions known to be effective in PPHN, the presence of associated anomalies of the gastrointestinal, genitourinary, and cardiovascular systems, and occasionally by onset beyond the early neonatal period. Histologic evaluation of lung tissue is the current gold standard for diagnosis and is most often performed at autopsy. Early ante mortem surgical lung biopsy can also provide the diagnosis, but the index of suspicion among health-care providers must be high. The FOXF1 gene has been identified as being responsible for ACD/MPV in 40% of cases examined, and additional candidate genes and potential defects are being investigated. We recommend development of an expanded registry to improve our understanding of the ACD/MPV phenotype, pathophysiology, and genetics.