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. Lymph contains cellular components (lymphocytes), protein, coagulation factors, and chylomicra. Lymphatic flow per unit of weight in the fetus is about five times that of the adult.

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.

Fetal chylothorax = the most prevalent form of fetal hydrothorax (65%)

  • occurs in 1:15,000 pregnancies
  • male:female ratio of 2:1
  • more frequently on the right side
  • accumulation of chyle (lymphatic fluid) within the pleural space
  • may be detected prenatally or within the neonatal period
  • most frequent cause of pleural effusions in the neonatal period
  • may lead to pulmonary hypoplasia

Accumulation of a large volume (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 (survival 30% – 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 associated with Chylothorax

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.

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).

Infantools | Chylus
Chylus derived from the pleural space (congenital chylothorax)

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.

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).

THERAPY

Antenatal
To allow more lung growth and decrease the interference of the accumulating fluid with venous return and cardiac function

  • allow more lung growth
  • decrease the interference of the accumulating fluid with venous return and cardiac function
  • thoracentesis
  • pleuro-peritoneal shunting
  • pleurodesis (creation of pleural adhesions)

Postnatal
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 connections

  • drainage of > 10 ml/kg/day (high volume)
  • loss of cells (especially lymphocytes),
  • proteins (including nutritious elements)
  • electrolytes
  • immune factors
  • 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.

Malnutrition, dehydration, nosocomial infections => periodic intravenous immunoglobulin (IVIG)

Cessation of enteral feeding and using parenteral nutrition, or using a formula whose fat source is primarily medium-chain triglycerides (MCT). The use of modified (defatted) breast milk has shown a reduction in pleural fluid drainage volume similar to MCT formulas.

A somatostatin analog (Octreotide) is another therapy used to reduce lymphatic flow, presumably by inducing splanchnic vasoconstriction, decreasing hepatic venous flow, and decreasing pancreatic and gastric secretions. Side-effects and complications include hyperglycemia, necrotizing enterocolitis (in preterm infants), biliary sludging, hypothyroidism, and pulmonary hypertension.

Infantools | Medication Icon

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)

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].

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.

For a patient who is born with resolved prenatally diagnosed CC, feeding breast milk and monitoring for re-accumulation of chylothorax 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 parenteral 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 treatment choices [42]. Forming collaborations to pool data and share experiences might help to achieve evidence-based treatment of CC.

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

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