Chylothorax

Lymph is generated in the interstitium and carried in lymphatic vessels in a unidirectional flow, joining the venous system near the junction of the left internal jugular and the left subclavian veins. There is variation in the thoracic lymphatic duct anatomy; most often (about 60%) there is a single right lymphatic duct along the right posterior mediastinum between the aorta and azygos vein that crosses to the mediastinum left of the esophagus and behind the aortic arch at the level of the fourth to sixth thoracic vertebrae.

Lymph contains cellular components (mainly lymphocytes), protein, coagulation factors, and chylomicra. Lymphatic flow per unit of weight in the fetus is about five times that of the adult. The total volume of lymphatic fluid is about 1 mL/kg; the flow through the thoracic duct in the adult is about 100 mL/h with two-thirds of the fluid generated by the liver and intestine. Lymphatic flow rate is affected by diet, medications, and other factors, and may increase 2-10-fold for a few hours following ingestion of dietary fat. Long-chain fatty acids are emulsified by bile acids to form fat globules, converted to chylomicra in the enterocytes, and absorbed by lymphatic capillaries called lacteals. Short- and medium-chain fatty acids are absorbed directly into the portal venous circulation without micelle formation.

Conditions associated with impaired lymphatic flow include congenital pulmonary malformation (CPAM) or increased central venous/superior vena cava pressure => leading to lymphatic leakage into spaces along the route of the lymphatic vessels (the pleural and pericardial spaces).

Fetal chylothorax, the most prevalent form of fetal hydrothorax (65%), occurs in 1:15,000 pregnancies, has a male:female ratio of 2:1, and occurs more frequently on the right side. Congenital chylothorax (CC) is an accumulation of chyle (lymphatic fluid) within the pleural space, and may be detected prenatally or within the neonatal period. It is estimated to occur in about one per 10,000 live births and is the most frequent cause of pleural effusions in the neonatal period.

Fetal chylothorax may compromise the space available for fetal lung growth and lead to pulmonary hypoplasia. This space occupation may also compromise vascular flow, causing heart failure and even hydrops fetalis. Accumulation of a large fluid volume in the pleural space or drainage of the effusion leads to the loss of

  • lymphocytes
  • antibodies
  • complement
  • coagulation factors
  • nutrients and fluid

Complications associated with chylothorax

  • Mass effect
  • Hypoplastic lungs
  • Compromised pulmonary function
  • Compromised venous flow and heart failure
  • Loss of lymphatic fluid components
  • Dehydration
  • Malnutrition
  • Vascular clotting
  • Infections

The prognosis for a fetus with CC depends upon the etiology and the presence of other anomalies, gestational age, and on the degree of pulmonary hypoplasia, with overall survival ranging from 30% to 70%.

Etiologies of Congenital Chylothorax

  • Thoracic anomalies
  • Congenital pulmonary malformations
  • Congenital diaphragmatic hernia
  • Pleural effusions
  • Lymphatic anomalies
  • Lymphangioma
  • Lymphangiomatosis
  • Lymphangiectasia
  • Congenital lymphatic dysplasia syndrome

Lymphatic Developmental Anomalies

These anomalies associated with chylothorax may be limited to the lungs or involve other organ systems. Chylothorax is usually caused by sluggish lymphatic drainage and/ or by mass formation that impedes drainage.

Lymphangiomas are focal proliferations of lymphatic capillaries. They may be present at birth as sponge-like or cystic. They grow slowly and rarely resolve spontaneously. There are several forms of lymphangiomas. The cavernous form consists of micro-cystic vessels. The macro-cystic form is known as cystic hygroma, mostly (75%) occurring in the head and neck region. Cystic hygroma may impinge on the airways and may resolve prenatally (neonatal treatment is excision and the use of a sclerosing agent). Neonatal treatment of cavernous lymphangioma is accomplished with laser therapy. Lymphangiomas in the mediastinal and pericardial areas may cause pericardial and pleural effusions.

Lymphangiomatosis is characterized by the presence of multiple lymphangiomas that infiltrate different tissues, including the lungs and other thoracic tissues. It is extremely unusual to diagnose this condition in the neonatal period.

Lymphangiectasia is characterized by dilation along the course of lymphatic vessels, but the number of vessels is normal. It may be a primary developmental defect or secondary to obstruction of lymphatic flow. Pulmonary lymphangiectasia may radiographically resemble pulmonary interstitial emphysema. Although pulmonary lymphangiectasia is reputed to be fatal, there are reports of infants born with CC who later had histologic diagnosis of pulmonary lymphangiectasia and survived. Survival has been reported in infants diagnosed with localized congenital pulmonary lymphangiectasia, who also had a clinical presentation similar to congenital lobar emphysema.

Congenital lymphatic dysplasia syndrome is an inherited form of a lymph vessel anomaly associated with CC without an identifiable cause. Lymphatic dysplasia associated with lymphedema is attributed to several possible etiologies. The majority of those with lymphedema have hypoplasia or aplasia of the peripheral lymphatic vessels, and some have lymphatic valvular incompetence causing chyle to reflux from the thoracic duct. Lymphatic dysplasia is a rare cause of CC reported in association with chylous ascites and lymphedema and described in patients with refractory CC associated with trisomy 21.

Lymphatic disorders are sometimes associated with syndromes such as Turner, Noonan, trisomy 21, and Ehlers-Danlos. Most cases with Turner syndrome (>60%) have lymphedema, more usually located in the hands and feet, because of underdevelopment of lymphatic capillaries (peripheral lymphatic aplasia or hypoplasia as the main pathologic process in addition to lymphatic valvular incompetence). The lymphedema often resolves in early childhood.

The International Society for the Study of Vascular Anomalies (ISSVA) published another classification of vascular anomalies, identifying lymphatic anomalies as lymphatic malformations. Lymphatic malformations are further described as cystic (macro-cystic and micro-cystic), generalized lymphatic anomaly, lymphatic malformations in Gorhame-Stout disease, channel-type lymphatic malformations, primary lymphedema, and others.

DIAGNOSIS

Chylous fluid

Chylous fluid is clear in the unfed patient, but appears creamy if the patient has been fed. The fluid contains >1000 white blood cells per μL with > 70-80% lymphocytes. It has a similar protein content to plasma, and a triglyceride concentration >1000 mg/dL (in feeding patients).

Etiology of Chylothorax

Prenatal evaluation to determine an etiology, plan a treatment strategy, direct parental counseling, and predict the prognosis includes fetal evaluation for chromosomal, cardiac, and thoracic structural anomalies, and evaluations of the mother for immunologic and infectious etiologies of hydrothorax.

Imaging techniques are listed below

Open lung biopsy is considered the gold standard in the diagnosis of certain conditions (congenital pulmonary lymphangiectasia).

Imaging

  • Lymphangiography requires cannulation of lymphatic vessels and can identify leaks from the thoracic duct. It provides the best anatomic detail of lymphatic vessels. It utilizes injection of an oil-based contrast agent, ethiodized oil, which has a high viscosity that may cause occlusion of the lymphatic vessels (water-soluble contrasts leak from the lymphatic vessels quickly), and the study may impose a risk of systemic emboli. The method was used to occlude lymphatic vessels as a therapeutic agent in several cases of congenital pulmonary lymphangiectasia. Lymphangiography is not advised when lymphatic dysplasia is suspected because the study may contribute to further damage of lymphatic vessels.
  • Magnetic resonance (MR) lymphangiography, a non-invasive method, was considered better at identifying lymph nodes but not especially good for evaluating lymph channels. Non-contrast MR lymphangiography and dynamic contrast MR lymphangiography enables visualization of central lymphatic anatomy and flow dynamics (with better resolution).
  • Lymphoscintigraphy (in which a radioisotope is injected between digits) can identify thoracic duct injury and aplasia and hypoplasia of lymphatic vessels. It provides less anatomical detail than conventional lymphangiography but may be useful in cases of lymphatic dysplasia.
  • Non-ionizing lymphography using subcutaneous indocyanine green (ICG) injections and obtaining fluorescent images of the extremities and the trunk has been used to quantify the severity of lymphatic dysplasia (minimally invasive bedside technique to visualize more superficial vessels but less accurate than lymphoscintigraphy, which can identify both superficial and deep lymphatic vessels).

Somatostatin

→ surface active agent
→ prevents alveoli from collapse at the end of expiration
→ produced and recycled by pneumocytes II during the second half of pregnancy
→ composed of 90% phospholipids (phosphatidylcholine = lecithin + phosphatidylglycerol) and 10% proteins (SP-A/B/C/D)

THERAPY

Antenatal

The goals for prenatal interventions are to allow more lung growth and development and to decrease the interference of the accumulating fluid with venous return and cardiac function. Pre- natal treatments include thoracentesis, pleuro-peritoneal shunting, and pleurodesis (creation of pleural adhesions) (Table 1). Compli- cations associated with prenatal interventions and the lack of convincing proof of efficacy has led to expert consensus opinions to reserve invasive interventions to fetuses with hydrops fetalis (Fig. 3) and to those without other major congenital anomalies [24], taking into account that some pleural effusions resolve spontane- ously. The Society of MaternaleFetal Medicine published guidelines for prenatal evaluation and intervention for pregnancies with non- immune hydrops fetalis (which accounts for 90% of hydrops, with lymphatic dysplasia accounting for 5e6% and fetal thoracic ab- normalities such as CPAM another 6%), including the role of pleuro- amniotic shunts [25]. Prenatal interventions to improve survival are considered for large bilateral chylothoraces and when chylothorax is associated with hydrops fetalis [21,25,30,31]. Lee et al. found that survival of neonates with CC and fetal chylothorax (of comparable severity) was significantly higher in the group that underwent prenatal intervention [30].

In a large German case series, 78 fetuses underwent pleuro- amniotic shunts for hydrothorax (excluding those associated with lung lesions such as congenital cystic lesions and congenital dia- phragmatic hernia); the mean gestational age for shunt placement was 26.5 weeks; 88.5% were born alive and 59% survived. Poly- hydramnios, hydrops placentae, birth within 4 weeks of the pro- cedure, and lower gestational age were among the factors associated with mortality. Resolution of hydrops following inter- vention was associated with improved survival [21].

Litwinska et al. summarized their experience with thoraco- amniotic shunts to drain large cysts in CPAM and combined their findings with those reported in the literature. They concluded that fetuses with hydrops had a lower survival rate (53/69, 77%) than those without hydrops (37/41, 90%) [32]. In a large (n 1⁄4 75) case series, Peranteau et al. reported outcomes of fetuses who were treated with thoraco-amniotic shunts for pleural effusions or cystic lung lesions. Gestational age at birth and resolution of hydrops fetalis were associated with improved survival [33].

Postnatal

The goal of neonatal treatment is to decrease the chylothorax volume to keep the pleural space clear and to allow time for injured lymphatic vessels to heal or to develop enough collateral connec- tions [2]. A stepwise treatment strategy is used. Progression in the risk and invasiveness of the treatment options is determined by response to the treatments, measured by volume of drained chy- lothorax (drainage of >10 mL/kg/day is considered a high volume), as well as the degree of interference with pulmonary function [2,4].

Drained lymphatic fluid causes loss of cells (especially lym- phocytes), proteins (including nutritious elements), electrolytes, and immune and coagulation factors. Drained fluid is partially replaced (usually with a 5% albumin solution). Both pro- and anticoagulation factors are lost in the drained lymphatic fluid and a shift towards increased risk for thrombosis may occur. This, in turn, is associated with decreased plasma antithrombin activity [34]. Acquired antithrombin deficiency is also known to occur in asso- ciation with other conditions with microvascular protein leakage [35].

As noted above, accumulation of a large pleural fluid volume or drainage of the effusion leads to the loss of lymphocytes [8], anti- bodies, complement, and coagulation factors, as well as nutrients and fluid. This may lead to malnutrition and dehydration [4]. There is an increased risk for nosocomial infections in patients with CC [8]. Some centers use periodic intravenous immunoglobulin (IVIG) administration as part of the treatment plan. However, in a small retrospective study, the use of IVIG was not shown to be effective in decreasing the risk of infection [36].

Other treatment options to decrease lymphatic flow include cessation of enteral feeding and using parenteral nutrition, or using a formula whose fat source is primarily medium-chain triglycerides (MCT) such as Enfaport®, and Portagen® (Mead Johnson Nutrition, Evansville, IN, USA) for enteral feeding. The use of modified (defatted) breast milk has shown a reduction in pleural fluid drainage volume similar to MCT formulas in a small controlled study and in a retrospective study [37,38].

A somatostatin analog (Octreotide; Norvis Pharmaceuticals, East Hanover, NJ, USA) is another therapy used to reduce lymphatic flow, presumably by inducing splanchnic vasoconstriction, decreasing hepatic venous flow, and decreasing pancreatic and gastric secre- tions. Side-effects and complications include hyperglycemia, necrotizing enterocolitis (in preterm infants), biliary sludging, hy- pothyroidism, and pulmonary hypertension [39]. Some in- vestigators have described possible benefits of this treatment in decreasing the volume of chylous effusions [40,41], but no trials have sufficiently evaluated safety or efficacy, and a Cochrane review did not find enough evidence to recommend treatment [39]. Church et al. could not find an advantage of octreotide treatment (n 1⁄4 45) over stopping feeding in a retrospective analysis in pa- tients with chylous effusions (some with CC but mostly following cardiac surgery) [42].

Surgical interventions include thoracic duct repair or ligation/ embolization, pleurodesis, pleuro-peritoneal shunts, and surgical excision of localized lymphangiomatosis or other masses contrib- uting to increased central venous pressure. Surgical intervention is considered after a period of time if more conservative therapies fail [2].

Other adjuvant therapies include medications to improve dia- stolic function for patients with elevated central venous pressure, and anticoagulation if a central venous thrombus is present. There are multiple case reports of therapeutic attempts with pharmaco- logic agents such as sirolimus, an immunosuppressive agent that has anti-angiogenic and anti-proliferative properties to treat diffuse lymphangiomatosis [23,29,43]. Inhaled nitric oxide, used for the treatment of persistent pulmonary hypertension, was hypoth- esized to decrease functional venous obstruction contributing to the persistence of post-surgical chylothorax [44]. Sildenafil was tried in the treatment of seven pediatric patients with cystic LM in the neck and abdomen (detected on average at a month of age) with encouraging results of decreasing mass size. The investigators admitted that the mechanism of sildenafil action was not clear and they proposed that the selective inhibition of phosphodiesterase-5 and lymphatic vessel relaxation might have played a role in the observed findings [45]. Defnet et al. summarized the current (observation, surgery, sclerotherapy, radiofrequency ablation, and laser therapy) and newer (sildenafil, propranolol, and sirolimus) therapeutic options for pediatric LM [23].

For a patient who is born with resolved prenatally diagnosed CC, feeding breast milk and monitoring for re-accumulation of chylo- thorax might be the appropriate treatment for the lowest severity of CC. On the other hand, de-escalating the level of treatment to defatted breast milk or MCT formula following response to a more aggressive therapy (cessation of enteral feeding and using paren- teral nutrition) or following a successful surgical intervention might be another example of matching improving severity to the level of intervention. More effort to evaluate the efficacy and side- effects of each treatment choice for the degree of CC severity might clarify the appropriate interval to transition between these treat- ment choices [42]. Forming collaborations to pool data and share experiences might help to achieve evidence-based treatment of CC.

Information about the clinical course of infants with CC is based mainly on data from single and multicenter case series and from survey analyses. Bellini et al. described the clinical course of 33 infants born with chylous effusions at multiple centers. Twenty- nine had CC requiring pleural drainage after birth; 22 survived to six months. All surviving patients were using an MCT diet at follow- up with good control of the chylous effusions. Two patients were treated with pleurodesis [24]. A small case series (10 patients) from California described a higher mortality in infants <34 weeks of gestation [46]. In another 10 patient series from Australia, the au- thors found that co-morbidities and chromosomal anomalies were associated with longer hospitalization. They treated six patients with octreotide and perceived a benefit from the treatment by having a decrease in the volume of chylous effusions [41].

An epidemiologic survey-based study in Germany in 2012 identified 28 cases of CC and reported on 27 cases with available records. Three patients died (11%), 25 (93%) required pleural drainage, 23 (85%) required mechanical ventilation, 25 (93%) received an MCT-based diet, and nine (33%) were treated with octreotide. Nine patients (33%) had other congenital anomalies, including Turner syndrome in five. The median gestational age at birth was 33 weeks. Two patients (7%) had venous thrombosis, and six (22%) had sepsis demonstrated by culture [7].

Practice points

  •   Prenatal interventions might improve survival in severe cases of fetal chylothorax.
  •   A stepwise approach that accounts for chylothorax severity and treatment risk levels is recommended.
  •   Prematurity, associated anomalies, and some congenital lymphatic anomalies are associated with worse outcomes.

REFERENCES

① Attar MA, Donn SM. Congenital chylothorax. Semin Fetal Neonatal Med. 2017;22(4):234-239. doi:10.1016/j.siny.2017.03.005