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Congenital Pulmonary Lymphangiectasia and Chylothorax – a Case Series

Congenital Pulmonary Lymphangiectasia and Chylothorax – a Case Series

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Lymphology 50 (2017) 188-196

CONGENITAL PULMONARY AND – A CASE SERIES

G. Rocha, P. Soares, I. Azevedo, M.J. Baptista, J. Casanova, C.S. Moura, H. Guimarães

Departments of Neonatology (GR,PS,HG), Pediatrics (IA), Pediatric (MJB), Cardiothoracic Surgery (JC), and Pathology (CSM), Centro Hospitalar São João, Porto; Faculty of Medicine (PS,IA,CSM,HG), University of Porto, Porto; and EpicUnit, Institute of Public Health (IA), University of Porto, Porto, Portugal

ABSTRACT lymphatic vessels (3). CPL can be divided into primary and secondary forms (3). The Congenital pulmonary lymphangiectasia primary congenital form presents in neonates (CPL) and chylothorax (CC) are rare and is usually fatal. Secondary forms result lymphatic developmental disorders. We report from a variety of processes that impair six clinical cases of CPL and CC that were lymphatic drainage, frequently related to admitted to our level III neonatal intensive lymphatic obstruction, cardiovascular care unit over the last 20 years. One case of obstruction, or associated with increased unilateral CC was successfully treated with production (3). Whereas most cases pleuro-amniotic shunt; three cases of bilateral are sporadic, there have been familial cases CC were associated to hypoplasia, reported and associations with congenital hydrops fetalis, and generalized lymphangi- anomalies and Noonan, Ulrich-Turner, Down ectasias; one case of CPL was associated with as well as other syndromes (2,4-7). CPL obstructive congenital defect; one case may occur isolated or in a generalized form of unilateral CC was successfully treated with associated to intestinal lymphangiectasia, thoracocentesis and medium-chain hemihypertrophy, and (7). diet. Mortality was high (66.6%). Although the exact incidence of CPL is unknown, autopsy studies suggest that 0.5-1% Keywords: Congenital pulmonary lymphan- of who are stillborn or die in the giectasia, chylothorax, lymphangiectasia, neonatal period have CPL (8). lung hypoplasia, hydrops fetalis, congenital We report on the six clinical cases of heart defect CPL and CC that were admitted to our level III neonatal intensive care unit over the last Congenital pulmonary lymphangiectasia 20 years. Our unit admits about 400 newborns (CPL) and congenital chylothorax (CC) are per year and is a referral center for cardiac, rare lymphatic developmental disorders (1). thoracic, and neonatal surgery. CPL is associated with dilation of the pulmo- nary lymphatics that drain the subpleural CASE REPORTS and interstitial spaces of the lung (1,2) and CC is a associated to Case 1 anomalies of the thoracic duct or multiple 189

A 37 week gestational age, birth weight until D5. A was 2990g male was born by C-section and inserted on D10 in the internal jugular . admitted for CC. During , a She died on D11 after a sudden pulmonary voluminous right pleural effusion was hemorrhage. The autopsy revealed cardiac diagnosed on obstetrical echography at 25 tamponade as a of the central weeks of gestation, and a pleuro-amniotic venous catheter and as the cause of death, shunt was placed at 30 weeks of gestation. and the presence of lung lymphangiectasias The Apgar score at birth was 9/10 (1st/5th complicated by chylothorax, as well as small minutes) and the drain was clamped and areas of mediastinal, pancreatic, and removed by five minutes of life, after mesenteric lymphangiectasias. collecting a sample of fluid for analysis, which confirmed the diagnosis of chylothorax Case 3 (1,100 white blood cells per ml with 94% ). The chest x-ray revealed a A 30 week gestational age, 1530g birth small right pleural effusion that resolved weight male newborn, delivered by C-section spontaneously by day (D) seven of life. The was admitted for prematurity and hydrops child did not need ventilatory support nor fetalis. Infectious, genetic, and metabolic . On D2 he was started on a diet studies collected by amniocentesis were not containing medium chain . The revealing; the karyotype was 46,XY. He echocardiographical evaluation revealed a needed resuscitation with intravenous functionally and structurally normal heart adrenaline and thoracocentesis that revealed and no other congenital anomalies were a bilateral CC (1,051 white blood cells per ml detected. The blood karyotype was 46,XY. with 88.5% lymphocytes). The Apgar score He was discharged on D7 of life and the was 1/1/2 (1st /5th/10th minutes). Bilateral subsequent outcome was good. pleural drains were inserted and was started (1 mcg/kg/day, with daily Case 2 increase of 1 mcg/kg to a maximum of 10 mcg/kg/day). He needed dopamine perfusion A 32 week gestational age, birth weight during the first 12 hr of life for . 2010g female was born by C-section after an Two doses of surfactant were given and echographical diagnosis of hydrops fetalis rescue high frequency oscillatory ventilation was made. She needed resuscitation at birth was needed for hypercapnia. An intraventri- with intravenous adrenaline and was started cular and parenchymal cerebral haemorrhage on mechanical ventilation. The Apgar score was detected at 24 hr of life on cranial was 2/5/6 (1st /5th/10th minutes). A bilateral . He died on D2. The autopsy thoracocentesis was performed and 30 ml of revealed pulmonary hypoplasia, bilateral pleural fluid were aspirated from each side chylothorax, dilation of lymphatic vessels of of the thorax. The analysis of the fluid was the , , , but also in the compatible with a chylothorax (1,573 white skin, kidneys, and mesentery, compatible blood cells per ml with 99% lymphocytes), with congenital lymphatic dysplasia. and a bilateral drain was placed on. Because of a significant bilateral drainage, octreotide Case 4 was started (1 mcg/kg/day, with daily increase of 1 mcg/kg to a maximum of 10 A female singleton of 3200 grams was mcg/kg/day). Infectious, metabolic and delivered at 39 weeks gestation by vaginal genetic studies did not reveal the cause of delivery. She evolved with sustained refractory hydrops; the blood karyotype was 46,XX. not responsive to high frequency Inotropic support with dopamine was needed oscillatory ventilation, administration of 190

Fig. 1. X-ray of diffuse congenital lymphangiectasia (clinical case number 4). surfactant, inhaled and vaso- pressor therapy. The chest X-ray revealed a pleural effusion on thorax x-ray and severe diffuse homogeneous bilateral reticular echography. The Apgar score at birth was image (Fig. 1). A complete echocardiographic 9/10 (1st and 5th minutes, respectively) and evaluation did not allow the exclusion of a the baby was breathing normally in room air. total anomalous pulmonary venous return A thoracocentesis was performed with aspira- and a was performed, tion of 20.5 ml of a citrine fluid, analysis of which identified a probable pulmonary which confirmed a CC (1,530 white blood associated with a cells per ml with 98.8% lymphocytes). He persistence of the fetal circulation. She died was started on octreotide (1 mcg/kg/day, with on D2. The autopsy of the newborn described daily increase of 1 mcg/kg to a maximum of findings of diffuse congenital pulmonary 10 mcg/kg/day), (six lymphangiectasia (Figs. 2,3) and pulmonary days), and a diet with medium-chain venous drainage to the left through triglycerides. The pleural effusion totally two ostia, one right and one left (variant of regressed, and the baby was discharged home normal), but with small-caliber pulmonary on D13 of life with follow up in the outpatient . The blood karyotype was 46,XX. department for nutritional support. The study was negative for Case 5 and the karyotype was 46,XX. Cranial, cardiac, kidney, and abdominal A 36 weeks preterm female pheno- echographical evaluations were normal. typically normal newborn, birthweight 2630 g, born by C-section of a 27 year old Case 6 primigravida was transferred on D1 to our center because of a moderate volume right A 34 weeks gestational age male preterm 191

Fig. 2. Hematoxylin-eosin stained lung parenchyma tissue demonstrating marked cystic dilatation of pulmonary lymphatics in interlobular septa (clinical case number 4).

Fig. 3. Hematoxylin-eosin stained lung parenchyma tissue displaying marked cystic dilatation of pulmonary lymphatics beneath the pleura, within interlobular septa, and in peribronchiolar regions (clinical case number 4). 192

Fig. 4. X-ray image demonstrating bilateral pleural effusions from congenital bilateral chylothorax before drain placement (clinical case number 6). was born by elective C-section to a 36 years giomatous lesion in the thorax was also old primigravida because of hydrops fetalis unremarkable except for bilateral pleural with voluminous bilateral pleural effusions effusions. Because of the voluminous associated with lung hypoplasia (Fig. 4). drainage the child needed several albumin Pregnancy was normally followed with infusions, plasma and human immuno- unremarkable obstetrical echographical globulin. Acid-base equilibrium was evaluations until 30 weeks of gestation. At consistently in the normal range. On D43, birth, the baby weight was 3760g (over 97th he underwent thoracic duct surgical ligation percentile) and generalized oedema was with abrasion of the right pleura. A lung evident. He needed resuscitation with positive biopsy was performed at this time and the pressure, 100% oxygen, tracheal intubation lung histological study did not reveal and mechanical ventilation. The Apgar score lymphangiectasias nor any other changes. was 4/7/8 (1st, 5th, 10th minutes). A bilateral The bilateral pleural effusion drainage did thoracocentesis revealed a voluminous CC not reduce significantly after the surgical (1,230 white blood cells per ml with 95% ligation and became more significant on left lymphocytes). Bilateral thorax drainage, side. On D70, a second surgical intervention octreotide infusion (1 mcg/kg/day, with daily with ligation of several thoracic collateral increase of 1 mcg/kg to a maximum of 10 vessels and abrasion of left pleura was mcg/kg/day), and parenteral nutrition were performed with a significant reduction of started. Daily drainage was voluminous, the pleural drainage. On D76, the child died almost 100 ml/kg per day, predominantly on due to fulminant septic shock caused by the right side, with a very slow improvement Klebsiella and Haemophilus over several days. A lymphscintigram was influenzae. Blood karyotype was 46,XY, normal, and an angio-tomographic study of Noonan syndrome study was negative, and the thorax performed to exclude a lymphan- CGH-arrays were normal. Cranial, 193 abdominal and renal ultrasound evaluation immediately after birth due to respiratory and 2D-echoardiogram did not show failure. is due to loss of congenital malformations. Autopsy revealed lymphatic fluid drainage associated with a severe form of lymphatic dysplasia decreased lung compliance and failure of affecting the lungs, spleen, mesentery, colon, lung inflation at the time of birth (10). The pancreas and portal spaces of the liver, as mechanical role of lymphatics in a developing well as dilation of lymphatic vessels around lung is likely to overlap both temporally and lymphatic nodes in general. functionally with that of pulmonary surfac- tant, and inadequate lymphatic function may DISCUSSION contribute significantly to the respiratory distress syndrome experienced by premature In this series the authors report their infants (10). experience with the rare cases of CPL and Treatment of CPL is mostly supportive CC in the neonatal period (summarized in including ventilatory support, drainage of Table 1). The identification of lymphatic pleural effusions, metabolic and nutritional vessels at autopsies was based on the correction, inhaled nitric oxide and vaso- morphology and, in the case of doubt, using pressor support for pulmonary , an immunocytochemical study with D2-40. extracorporeal membrane oxygenation for The etiology of CPL may be related to failure selected cases, and surgical resection may be of regression of the large lymphatic vessels curative in some cases (2-4,7). that are normal during the maturation CC was the commonest lymphatic development process at 9-16 weeks of gesta- anomaly reported in this series in cases 1,2,3,5, tion (7). In some cases, CPL may occur in and 6. In three cases it occurred associated to association to chylothorax, and non-immune hydrops fetalis, generalized lymphangiectasias, fetal hydrops may develop during the fetal and mortality (cases 2,3, and 6). period as in the reported cases 2,4 and 7 (7). The favorable evolution of the clinical CPL should be distinguished from diffuse case 1 with MCT diet could be explained by pulmonary which is the natural tendency for spontaneous characterized by an increased number of remission of congenital chylothorax as the complex anastomosing lymphatic channels thoracic duct matures. In this particular case, with secondary variable dilation or expansion the diagnosis of fetal pleural effusion was within the lungs and mediastinum. In noted by 25 weeks of gestation, i.e., twelve contrast, the lymphatic vessels in CPL are weeks before birth (at 37 weeks). This long normal in number and are relatively more period may have provided enough time for a regular in size and shape (7). spontaneous cure. The prevention of tissue is CC results from multiple lymphatic considered a universal role of anomalies or thoracic cavity defects vessels in all tissues except the central nervous and may accompany other congenital system although even there the lymphatics anomalies and genetic syndromes. Fetal probably function similarly. Also, lymphatics chylothorax occurs in 1:15,000 play specialized roles in coordinating and has a male: female ratio of 2:1 and occurs adaptive immune responses in secondary more frequently on the right side (11). Fetal lymphoid organs and in transport of dietary chylothorax may increase the risk of death as from the intestine (9). it compromises lung development, pulmonary, Animal studies have shown that and cardiovascular function and also is lymphatic function is required prenatally for complicated by the loss of drained lymphatic lung inflation at birth (10) and lymphatic- contents. Prenatal interventions such as deficient animals are susceptible to die pleuroamniotic shunting might improve 194 TABLE 1 Summary of the Seven Clinical Cases Congenital Pulmonary Lymphangiectasia and Chylothorax 195 survival in severe cases of fetal chylothorax. , and cor triatum have already been The neonatal treatment strategy is generally described in association with CPL (7). supportive with interventions that include Previously, CPL has been almost thoracostomy drainage and attempts to uniformly fatal (3). Although with this poor decrease flow using a stepwise approach prognosis, improved outcomes, possibly as that begins with the least invasive means as the result of advances in neonatal and octreotide or somatostatin administration, pediatric intensive care medicine have been parenteral nutrition and a diet containing reported (12). The rarity of CPL makes it medium-chain triglycerides. Administration difficult to ascertain specific figures for of albumin, coagulation factors and immuno- mortality and survival but although optimism globulins may be needed in volumous chyle regarding survival cannot be justified in losses. Surgical interventions are reserved for the face of manifestations of CPL, such as severe prolonged cases and include thoracic hydrops fetalis, chylothorax and severe duct ligation or embolization, and neonatal respiratory distress, the outcome of pleuroperitoneal shunting. Evidence-based CPL need no longer be viewed as pessimis- treatment choices are lacking and are much tically as it once was, particularly in the needed (11). Most cases of congenital chylo- absence of co-morbidities, such as congenital thoraces resolve with time. Prognosis depends heart disease (13). on the etiology, presence of other congenital Our mortality was high (66.6%) compared anomalies, gestational age, complications to literature and one case associated with arising during the neonatal period, and the congenital heart disease died. degree of pulmonary hypoplasia, with an overall survival ranging from 30% to 70% CONCLUSION (11). In our series including five CC, three (60%) died. Expertise in performing In this series, CC was the most prevalent lymphatic studies is not universally available, lymphatic anomaly and was associated and data on both efficacy and safety of the with generalized lymphatic dysplasia and various therapeutic options are needed to hydrops fetalis in three cases. Hydrops fetalis determine the best approach to the treatment and generalized lymphatic dysplasia were of CC (11). associated to a poor outcome of congenital Secondary CPL may be caused by chylothorax. The association of CPL with an cardiac lesions as the result of obstruction to obstructive cardiac defect was also noted to pulmonary venous flow, or cardiac lesions have a poor prognosis. which have been hypothesized to interfere with the normal regression of the lymphatic CONFLICT OF INTEREST AND tissue elements after the 16th week of fetal DISCLOSURE life (7). Left-sided obstructive congenital malformations of the heart have been reported All authors declare that no competing in 60% of neonates with CPL at autopsy (7). financial interests exist. In this series, one case of CPL was associated with obstructive congenital cardiac anomaly (case 4), although in this case the lymphatic REFERENCES dilation was considered by the pathologist as an anomaly not related to the obstructive 1. Esther, CR, PM Barker: Pulmonary cardiac malformation since the pulmonary lymphangiectasia: Diagnosis and clinical course. Pediatr. Pulmonol. 38 (2004), 308-331. veins were not enlarged. 2. 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