Introduction

First described by Wagenvoort in 1978, pulmonary capillary hemangiomatosis (PCH) is a rare vascular lesion that causes pulmonary hypertension which may or may not be related to pulmonary venous obstruction [1]. It is pathologically characterized by uncontrolled proliferation of alveolar capillaries which infiltrate into the alveolar septae, bronchioles and pulmonary parenchyma [2]. It has also been associated with a number of autoimmune diseases including systemic lupus erythematosus and Takayasu arteritis. PCH is extremely rare in children with most cases occurring sporadically with the exception of one reported case of familial PCH [3]. Congenital diaphragmatic hernia (CDH) is a congenital anomaly in which abdominal viscera herniate into the chest cavity leading to high mortality and morbidity secondary to pulmonary hypoplasia and pulmonary hypertension [4]. Although both CDH and PCH have been associated with other congenital abnormalities, a thorough search of OMIM did not show any syndromes in which both conditions have been reported together. Here, we present an interesting case of a child with prenatally diagnosed CDH complicated by severe pulmonary hypertension and PCH diagnosed on post-mortem examination.

Case

A male infant, with a prenatal diagnosis of CDH, was born at 34 2/7 week gestation via cesarean section (birth weight, 2380 g). He was initially diagnosed with a severe left CDH at 18 weeks gestational age. Fetal magnetic resonance imaging revealed a CDH with liver herniation and a lung-to-head ratio (LHR) of 0.8 (Fig. 1). Given the severity of the CDH, the fetus underwent an uncomplicated fetal endoscopic tracheal occlusion at 28 1/7 week gestation. He was delivered due to uncontrolled preterm labor with removal of the tracheal occlusion at the time of delivery by a modified ex-utero intrapartum (EXIT) procedure. Apgar scores were 4 and 6 at 1 and 5 min, respectively. He was supported with mechanical ventilation. He did not require extracorporeal membrane oxygenation but received inhaled nitric oxide for pulmonary hypertension.

Fig. 1
figure 1

Fetal MRI at 26 3/7 days gestation illustrating severe left congenital diaphragmatic hernia with a portion of the liver and viscera in the left chest (arrow)

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On the fifth day of life, he had remained relatively stable and underwent repair of the left CDH and remained intubated. Serial echocardiographic evaluation after birth demonstrated persistent pulmonary hypertension, dilated main pulmonary arteries, severely dilated right ventricle and right atrium. The patient’s pulmonary hypertension remained severe throughout the hospital course necessitating management with multiple vasodilatory agents including sildenafil, inhaled nitric oxide and prostaglandins including epoprostenol and treprostinil. CT angiography of the chest demonstrated non-obstructed pulmonary veins and severe dilation of the main, right pulmonary arteries and a milder degree of dilatation on the left (Fig. 2). The patient continued to require ventilator support and had a tracheostomy performed at 3 months of age. He remained on multiple vasodilatory agents for his pulmonary hypertension until he succumbed to complications of bacterial sepsis at 4 months of age, following a prolonged stay in the neonatal intensive care unit (NICU). The events surrounding his death were notable for bacterial sepsis leading to significant metabolic acidosis and abdominal compartment syndrome necessitating an exploratory laparotomy. At the time of exploration, he was found to have ischemic bowel and was transferred back to the NICU with an open abdomen. The patient expired shortly after the operation.

Fig. 2
figure 2

CT angiogram of the chest performed at 1 month of life demonstrating severe dilation of the main, right pulmonary arteries (solid arrow) and a milder degree of dilatation on the left pulmonary artery (dashed arrow)

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Post-mortem examination of the heart showed cardiomegaly [83 g (31 g expected)], with marked dilation and moderate to marked hypertrophy of the right atrium and ventricle, consistent with cor pulmonale. The main and right pulmonary arteries were also dilated. The left lung was markedly hypoplastic, with a small collapsed right upper lobe. Histologically, there were abundant, dilated and congested capillaries expanding the walls of the alveolar septae (Fig. 3). In multiple areas, the airways were distorted by capillaries within the muscular layer and mucosa, focally forming polypoid protrusions into the lumen. Focal large pleural capillary aggregates were present and rare areas suggested intramural capillaries within arteries and veins. These findings were most accentuated in the right upper lobe. Pulmonary hypertensive changes included moderate medial hypertrophy in small muscular pulmonary arteries with focal fibrocellular intimal hyperplasia (Fig. 4). Minimal intimal fibrosis with no significant luminal obstruction was seen in the pulmonary veins. Other lung findings included organizing pneumonia and architectural changes of chronic neonatal lung disease, most prominent in the hypoplastic left lung. There were no other hemangiomas noted in other organs.

Fig. 3
figure 3

Marked pulmonary capillary proliferation

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Fig. 4
figure 4

Small pulmonary artery with thickened intimal and medial layers

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Discussion

PCH is a rare disease that is associated with pulmonary hypertension, hemoptysis and an overall poor prognosis [5]. Patients with PCH often present with pulmonary hypertension and signs of right heart failure. Given its rarity, PCH is difficult to diagnose based on clinical or radiographic imaging alone. The diagnosis is often established post-mortem or by lung biopsy with the pathognomonic finding of proliferation of capillaries that form nodules and invade pulmonary vessels and airways [6]. In children, PCH is a rare cause of pulmonary hypertension and has only been reported in a few case reports or series [2, 5, 7, 8]. Of these cases, presentation in the neonatal period is unusual.

Although, PCH has been linked to congenital anomalies including renal agenesis and congenital heart defects [5, 8]. We describe the first case of PCH in association with CDH. Certain genetic mutations including an autosomal recessive mutation in the eukaryotic translation factor 2 alpha-kinase 4 (EIF2AK4) have been implicated in the pathogenesis of PCH [9]. CDH has also been associated with genetic mutations [10] but there have been no mutations linking both conditions. Pulmonary hypertension that is seen in CDH is thought to be related to a decrease in the number of pulmonary vessels, thickening of the adventitial layer and medial hyperplasia which leads to inappropriate remodeling of the pulmonary vasculature in the postnatal phase [11]. PCH can be differentiated from primary pulmonary hypertension based on the striking, abnormal capillary proliferation that is absent in primary pulmonary hypertension. The etiology of PCH remains unknown but it is thought to either be a neoplastic process or a proliferative response to an angiogenic stimulus such as hypoxia [5, 6]. The case reported here lends itself to the latter theory given the fact that the pulmonary hypoplasia associated with CDH can lead to hypoxic events in the fetal lung. It has been shown that fetuses with severe CDH who undergo fetal tracheal occlusion (FETO) show an increase in the contralateral pulmonary vascular index, a measure of the entire vascularity of the lung following FETO [12]. The patient in the case presented underwent FETO for severe CDH. The constellation of severe CDH and treatment with FETO lend themselves to the proposed theory that PCH occurs due to an inciting event which in this case could be the CDH followed by the improvement of the patient’s hypoxia. However, there have been no reports of PCH in any of the non-survivors of FETO.

Treatment of pulmonary hypertension in infants with CDH takes places in a stepwise fashion that may result in the escalation of therapy to include vasodilatory agents such as inhaled nitric oxide and prostaglandins. Management of adults with PCH has been limited to lung transplantation or the guarded use of epoprostenol or systemic steroids [3]. A recent study by Ogawa et al. [13] showed that epoprostenol improved hemodynamic function in adult patients with PCH but the authors expressed the need for cautious use given the risk of pulmonary edema. In children, PCH has been managed with prostaglandins and systemic steroids. However, there is no standardized treatment strategy, likely due to the rarity of the condition. In the case presented, the patient received multiple agents for pulmonary hypertension including epoprostenol without the side effects of pulmonary edema.

Our case shows that PCH can occur early in infancy in conjunction with other congenital anomalies. A high index of suspicion, which is often needed for accurate diagnosis, may be shrouded by other causes of pulmonary hypertension such as CDH in our case. Although this report is limited by the unusual combination of CDH and PCH thus affecting its generalizability to a larger patient population, this case suggests that PCH should be included in the differential diagnosis when managing an infant with refractory, severe pulmonary hypertension. A lung biopsy considered earlier in the course of treatment will be diagnostic and guides expectations and outcomes. The rarity of PCH in children has led to a paucity of effective therapeutic options. Future studies that focus on the etiology and pathogenesis of PCH will help to establish its link to other conditions as well as effective management strategies.