Misalignment of Lung Vessels and Alveolar Capillary Dysplasia: A Case Report With Autopsy

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CASE REPORT
Misalignment of Lung Vessels and Alveolar Capillary Dysplasia: A Case Report With Autopsy
Shih-Pin Hung a,y, Shih-Hung Huang b,y, Chun-Hung Wu a, Wu-Charng Chen a, Ka-Em Kou a, Nan-Koong Wang a, Lung-Huang Lin a,c,*
aDepartment of Pediatrics, Cathay General Hospital, Taipei, Taiwan bDepartment of Pathology, Cathay General Hospital, Taipei, Taiwan cCollege of Medicine, Fu-Jen Catholic University, Taipei, Taiwan
Received May 31, 2010; received in revised form Sep 4, 2010; accepted Sep 20, 2010
Key Words alveolar capillary dysplasia; misalignment of lung vessels; persistent pulmonary hypertension of the neonate
* Corresponding author. Department Taiwan.
1875-9572/$36 Copyright ª 2011, Taiw doi:10.1016/j.pedneo.2011.05.010
Misalignment of lung vessels (MLV) with or without alveolar capillary dysplasia (ACD) is a rare cause of idiopathic persistent pulmonary hypertension of the neonate. This report describes a full-term infant with severe and intractable pulmonary hypertension. The patient’s condition progressively deteriorated despite high-frequency oscillatory ventilation, infusion of magne- sium sulfate, dopamine, and dobutamine to control blood pressure, and nitric oxide inhalation therapy. The infant died at 5 days of age. The diagnosis of MLV with ACD was established by autopsy. Histopathologic analysis revealed a failure of formation and an ingrowth of alveolar capillaries, thickening of the alveolar walls, poor contact of capillaries with alveolar epithe- lium, small intra-acinar muscularized arterioles, and anomalous pulmonary veins within bronchovascular bundles. The low rate of diagnosis of MLV with or without ACD may be because of the early high mortality rate or patchy involvement in some cases. Increasing awareness of this clinical entity may prevent the use of costly, invasive, and probably ineffective proce- dures. Short-term improvement after inhalation of nitric oxide does not lead to long-term survival but merely provides time for potential lung transplantation. Copyright ª 2011, Taiwan Pediatric Association. Published by Elsevier Taiwan LLC. All rights reserved.
of Pediatrics, Cathay General Hospital, No. 280, Section 4, Ren-ai Road, Da-an District, Taipei 106,
.tw (L.-H. Lin). g contributed equally to this study.
an Pediatric Association. Published by Elsevier Taiwan LLC. All rights reserved.
1. Introduction
Persistent pulmonary hypertension of the neonate (PPHN) is characterized by cyanosis and respiratory distress. It may be idiopathic or a complication of neonatal cardiorespira- tory disorders, including pneumonia, perinatal hypoxia, pulmonary hypoplasia, meconium aspiration syndrome, or hyaline membrane disease.1 Misalignment of lung vessels (MLV) with or without alveolar capillary dysplasia (ACD) may cause idiopathic PPHN.2e7 This report describes a neonate with severe and intractable PPHN without any other accompanying anomaly. Histopathologic analysis of lung tissues confirmed the diagnosis of MLV and ACD.
2. Case Report
A full-term male infant was born to a 27-year-old primi- gravida after an uneventful pregnancy. The infant was delivered by cesarean section because of placental abrup- tion and fetal distress. The birth body weight was 2860 g, and Apgar scores were 5 and 7 at 1 minute and 5 minutes, respectively. The patient developed increasing respiratory distress and cyanosis soon after birth. Arterial blood gas data were pH 7.157, PO2 49.4 mmHg, PCO2 52.9 mmHg, and HCO3 18.8 while breathing 30% oxygen. At 1 hour of age, the patient’s respiratory status deteriorated, with the devel- opment of cyanosis and bradycardia. The infant was intubated with mechanical support. Cardiopulmonary resuscitation was performed because of desaturation and bradycardia. Chest radiography revealed bilateral pneu- mothorax and pneumomediastinum (Figure 1). Thor- acocentesis was performed using angiocatheters. Antibiotic therapy with intravenous ampicillin and cefotaxime was administered. Septic work-up, including blood and cere- brospinal fluid cultures, was negative for abnormalities. Hypoxemia and acidosis persisted despite 100% oxygen supplementation. Congenital heart disease or PPHN was suspected. Two-dimensional echocardiography was per- formed, showing dilatation of the right atrium and right ventricle, main pulmonary artery dilatation, a large atrial bidirectional shunt through the patent foramen ovale, and
Figure 1 Chest radiography showed bilateral pneumothorax and pneumomediastinum.
a large right-to-left shunt through a large patent ductus arteriosus, with a pressure gradient of up to 35 mmHg. For evaluation of the severity of pulmonary hypertension, the right ventricular pre-ejection period to right ventricular ejection time (RVPEP/RVET) ratio was measured by M mode of echocardiography.8 According to the relationship between the RVPEP/RVET ratio and pulmonary artery end diastolic pressure (PAEDP), the normal range of RVPEP/ RVET ratio is less than 0.3, which indicates that the PAEDP ranges from 10 mmHg to 15 mmHg. In patients with pulmonary hypertension, the ratio may increase up to 0.35, which corresponds to the PAEDP being higher than 20 mmHg. In this patient, the RVPEP/RVET ratio was 0.5, which showed that the PAEDP was increasing definitely. All of these findings indicated suprasystemic pulmonary blood pressure. The patient’s condition progressively deterio- rated inspite of aggressive treatment for severe persistent pulmonary hypertension, including 100% oxygen supple- mentation, high-frequency oscillatory ventilation, infusion of magnesium sulfate, dopamine, and dobutamine to control blood pressure, and inhaled nitric oxide therapy. The infant died at age 5 days. With high awareness of the possibility of MLV and ACD, autopsy was performed after the parents provided informed consent. The heart and lung structures were unremarkable grossly except for right ventricle hypertrophy, patent foramen ovale, patent ductus arteriosus, and dilatation of the pulmonary trunk. Histopathologic analysis revealed a failure of formation and an ingrowth of alveolar capillaries, thickening of the alveolar walls, poor contact of capillaries with alveolar epithelium, small intra-acinar muscularized arterioles, and anomalous pulmonary veins within bronchovascular bundles (Figure 2).
3. Discussion
PPHN is characterized by a persistent right-to-left shunt causing severe hypoxemia. The estimated annual incidence is about 1 in 1000 live births.1 An overall mortality rate of 27.6% in Taiwan has been reported in the literature.9 MLV and ACD are rare causes of PPHN, with a poor prognosis and mortality rate in infancy of almost 100%.2e5 In this case, the diagnosis of MLV and ACD was established by autopsy findings.
MLV with or without ACD is a developmental disorder of lung vessels.2e4 It was first described in 1981 by Janney et al, who noted that “failure of the formation and ingrowth of alveolar capillaries led to absence of normal air-blood barriers” and “anomalous veins were present in the bron- chovascular bundles.”2 More than 80 pediatric cases and 1 adult case have been reported in the English-language literature.10 Al-Hathlol et al indicated a male predomi- nance, with a male-to-female ratio of 3:2.11 Most of the cases have been sporadic; about 10 familial cases (12% of cases) have been described, suggesting an autosomal recessive inheritance.5,6,10e15 In the literature, chromo- somal analysis was performed in three cases, which showed a normal karyotype.5,16,17 Using array comparative genomic hybridization analysis, Stankiewicz et al demonstrated six overlapping microdeletions encompassing the FOX tran- scription factor gene cluster in chromosome 16q24.1q24.2
Figure 2 Photomicrograph shows alveolar capillary dysplasia and misalignment of lung vessels. (A) Alveoli septa (arrow) are widened, with large centrally located venules surrounded by loose mesenchyme, haematoxylin and eosin stain, 40 original magnification. (B) The alveolar septa show poor capillaries apposition and density, staining by CD31 immunohistochemistry stain, 100 original magnification. (C,D) Anomalous pulmonary veins (v) within the adventitia of pulmonary arteries (a) and bronchioli (b), staining by (C) haematoxylin and eosin stain and (D) Masson’s trichrome stain, 100 original magnification.
234 S.-P. Hung et al
Misalignment of lung vessels 235
in patients with ACD, MLV, and multiple congenital anom- alies. Inactivating mutations of FOXF1 gene were also reported.18
Clinical manifestations of this disorder are typically severe and intractable PPHN, respiratory distress, and cyanosis, followed by progressive respiratory failure. In most cases, symptom onset is within 48 hours of birth, although a few cases had a late onset of 2e7 weeks of age and one reported case was diagnosed in an adult.10,12,19,20
Of cases affecting infants, 95% were full-term with appro- priate size for gestational age.11 About half of the patients had accompanying anomalies, including those of the gastrointestinal tract, the genitourinary tract, and the cardiovascular system.21e27 The frequencies of these accompanying anomalies were 40%, 32%, and 16%, respec- tively.11 Other rare associations have also been reported, such as anterior segment dysgenesis of the eyes, hemi- vertebrae, and phocomelia.5,22,24 Chest radiography is usually nonspecific, although in some reported cases it has revealed pneumothorax.2,5,6,14,17,21,25,28 Diagnosis is confirmed by autopsy or lung biopsy.15,19,22e24,29,30 Usually, the lung structure is gross, with some cases featuring abnormal lobation.5,13,21,23 Histopathologic analysis of MLV has revealed that anomalous pulmonary veins within the bronchovascular sheath parallel to the pulmonary arteries and bronchi, ACD present as absence or decrease of capil- laries adjacent to alveolar epithelium, thickening of the alveolar septum and medial hypertrophy of the small pulmonary arteries, and increased muscularization of the small intra-acinar arterioles.10 Furthermore, the immuno- histochemical staining of smooth muscle actin can be helpful for evaluating the increased muscularity of pulmonary arteries; whereas, the immunoreactivity of type IV collagen can demonstrate the fibrotic changes in the alveolar septa and common fibrous sheath.31 CD34 immunohistochemistry is helpful in detecting the capillary apposition and density.32
Involvement of the lung may be diffuse (85% of cases) or patchy (15%).11 ACD may occur with or without MLV, depending on the stage of development during the anoma- lies’ occurrence.17 Usui et al suggested the potential role of diagnosis by prenatal fetal ultrasonography, which revealed increasing lung echogenicity and polyhydramnios.33
The definite etiology of this anomaly is unknown. Failure of formation and ingrowth of alveolar capillaries leading to loss of normal air-blood barriers was proposed by Janney et al.2 Genetic influences, mutation, or teratogenic expo- sure in early pregnancy during embryogenesis may cause pulmonary vasoconstriction that interrupts normal angio- genesis.3,6,12,13,15,34 Vascular endothelial growth factors have also been suggested.35 A review of pulmonary pathology by deMello indicated that ACD probably reflects a disorder of vasculogenesis, whereas MLV suggests a disorder of sprouting or angiogenesis.36 Arterial muscu- larization may be a primary anomaly or secondary to hypoxemia induced by intrapulmonary shunting through the arteriovenous wall.4 Wallot et al reported a case with concurrent congenital alveolar proteinosis and MLV in consanguineous infants. They speculated that mutations in the surfactant protein B gene may influence vessel devel- opment, leading to MLV.15 However, there is no evidence of intrauterine infections or maternal distress related to ACD and MLV.
No specific treatment is available for ACD and MLV. The goal of management is to reduce the severity of PPHN. A review by Al-Hathlol et al indicated that tolazoline and alkalosis with sodium bicarbonate achieved transient improvement in PO2 in 50% and 20% of reported cases, respectively, whereas prostaglandin E1 and E2, nitroprus- side, diltiazem, dipyridamole, and magnesium sulfate were not effective.11 Inhaled nitric oxide, high-frequency oscillatory ventilation, and high-frequency jet ventilation achieved only a transient response.11,22,37 Extracorporeal membrane oxygenation was used in 41% of cases with MLV and ACD, but all these patients were died after wean- ing.11,23,38 Despite different strategies used for the management of hypoxia and pulmonary hypertension in cases of ACD and MLV reported in the literature, the mortality rate in infancy was almost 100%.
ACD and MLV are rare causes of idiopathic PPHN. The low rate of diagnosis may be because of the high mortality rate or patchy involvement in some cases. We described the first case of ACD and MLV without accompany anomaly, which was confirmed by autopsy in Taiwan. The patient presented as pneumothorax and severe idiopathic pulmonary hyper- tension immediately after delivery. The patient’s condition still deteriorated even though all the strategies for relieving pneumothorax and PPHN. Increasing awareness of this clinical entity may prevent the use of costly, invasive, and probably ineffective procedures. Inhaled nitric oxide therapy and extracorporeal membrane oxygenation merely provide time for potential lung transplantation.
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Misalignment of Lung Vessels and Alveolar Capillary Dysplasia: A Case Report With Autopsy
1 Introduction