Non-immune hydrops fetalis secondary to congenital chylothorax with diffuse interstitial lung disease: a diagnostic conundrum

Abstract

A Chinese male infant was born at 35 weeks weighing 2935 g to a mother with polyhydramnios and prenatal hydrops fetalis. He developed marked respiratory distress secondary to bilateral congenital chylothorax and required pleural drainage, high frequency oscillation and inhaled nitric oxide therapy. He was extubated to non-invasive ventilation by day 14. There was no bacterial or intrauterine infection, haematologic, chromosomal or cardiac disorder. He was exclusively fed medium-chain triglyceride formula. High-resolution CT showed diffuse interstitial lung disease. He received a dexamethasone course for chronic lung disease to facilitate supplemental oxygen weaning. A multidisciplinary team comprising neonatology, pulmonology, haematology, interventional radiology and thoracic surgery considered congenital pulmonary lymphangiectasia as the most likely diagnosis and advised open lung biopsy, lymphangiography or scintigraphy for diagnostic confirmation should symptoms of chylothorax recur. Fortunately, he was weaned off oxygen at 5 months of life, and tolerated human milk challenge at 6 months of life and grew well.

Background

Pleural effusion is a rare cause of respiratory distress in a neonate compared with transient tachypnoea and respiratory distress syndrome. Chylothorax is the most common reason for neonatal pleural effusion¹ and has an incidence ranging from 1 in 10 000 to 24 000.^{2 3} The diagnosis of chylothorax is made from biochemical examination of pleural fluid and characterised by triglyceride levels >1.1 mmol/L, cell count exceeding 1000 cells/μL with lymphocyte fraction of over 80%.^{1 4–6} Massive effusions at birth compromise venous return and is associated with pulmonary hypoplasia, persistent pulmonary hypertension and non-immune hydrops fetalis.² The causes of congenital chylothorax are heterogeneous and can be classified into genetic or syndromic disorders, thoracic developmental anomalies and pulmonary lymphatic abnormalities, including congenital lymphangiomatosis and congenital pulmonary lymphangiectasia (CPL).¹

Diffuse interstitial lung disease is a highly heterogeneous group of very rare lung disorders often with unknown aetiology. Children with diffuse interstitial lung disease may present with acute or chronic respiratory signs and may require open lung biopsy for histopathological diagnosis in cases of diagnostic uncertainty.⁷ In a young child, the causes include surfactant dysfunction, pulmonary developmental disorders, growth disorders, systemic disease, postinfectious conditions, neuroendocrine cell hyperplasia of infancy, pulmonary interstitial glycogenosis and a group of diverse conditions, which include pulmonary lymphatic abnormality.⁷

We present a newborn infant with non-immune hydrops fetalis secondary to bilateral congenital chylothorax who was later diagnosed with diffuse interstitial lung disease. The multidisciplinary team managing this rare complex case made a provisional diagnosis based on his clinical presentation and radiological imaging. Taking into consideration the disease trajectory of similar cases in the literature, the team devised a management approach, while weighing the benefits and risks of watchful waiting versus further invasive investigation to confirm the clinical suspicion with a view to definitive treatment. This case illustrates the importance of multidisciplinary team engagement and learning from the experience reported in the literature.

Case presentation

A male neonate conceived through in vitro fertilisation was born prematurely at 35 weeks 4 days gestation to a multiparous woman of Chinese descent. The pregnancy was complicated by prenatal hydrops fetalis associated with pleural effusion, polyhydramnios from 32 weeks gestation and a high amniotic fluid index (38 cm) a day before delivery. Fetal anomaly screening scan at 19 weeks was normal. Doppler study of the middle cerebral artery was normal, indicating no fetal anaemia. Maternal screen for toxoplasmosis, cytomegalovirus, herpes, HIV and syphilis was negative. She did not undergo amniocentesis because non-invasive prenatal testing indicated low risk. Parental relationship was non-consanguineous. Her first child aged 3 years was healthy.

A male baby was delivered by emergency caesarean section with Apgar scores of 3 at 1 min, 7 at 5 min and 9 at 5 min. Birth weight, length and head circumference were 2935 g, 47 cm and 35.5 cm, respectively, corresponding to the 76th, 55th and 98th centiles on standard intrauterine growth charts (Fenton et al).⁸ Because of marked respiratory distress, he was resuscitated by emergency intubation and ventilation at high pressures from 3 min of life, and admitted to the neonatal intensive care. The first arterial blood gas sample during ventilation at tidal volume of 5.5 mL/kg was satisfactory (pH 7.254, pCO₂ 55.2, pO₂ 83.9, base excess −4.3).

At birth, the baby appeared hydropic with severe oedema of the head/neck and mild oedema of the lower limbs. There was no facial dysmorphism and no evidence of pallor, jaundice or hepatosplenomegaly. Examination of the cardiovascular system revealed regular heart rate (150/min) with dual non-muffled heart sounds. Air entry was very poor with a dull percussion note bilaterally. Chest X-ray at birth confirmed bilateral pleural effusions (figure 1).

Figure 1.

(A) Chest X-ray on day 1 of birth demonstrates moderate volume right and small volume left apical pleural effusions (arrowheads). (B) Day 3 chest X-ray following insertion of right intercostal chest tube shows significant resolution of right pleural effusion with development of moderate left pleural effusion (white arrowheads). Both X-rays also show diffuse thickening of the chest wall soft tissues (black arrows), suggestive of hydrops fetalis.

Urgent bilateral thoracocentesis was performed, draining clear straw-coloured pleural fluid. Pleural fluid analysis showed a white cell count over 1 x 10ˆ⁹ cells/L and lymphocyte count 97%, consistent with a diagnosis of chylothorax.^1–3 A daily volume equivalent to 100 mL/kg (day 1), 73 mL/kg (day 2) and 26 mL/kg (day 3) was spontaneously drained from the right pleural cavity, while 7 mL/kg was drained from the left pleural cavity over the first 3 days of life. The chylothorax did not recur. He did not receive octreotide. Inotropic support with dopamine, epinephrine and milrinone infusion was started on day 2 for systemic hypotension and weaned off by day 8.

Investigations showed normal full blood count and metabolic studies. Peripheral blood karyotype was that of a normal male infant (46XY). Cord thyroid stimulating hormone at birth and a thyroid function test later were normal. He screened negative for intrauterine infections (toxoplasmosis, rubella, cytomegalovirus, herpes and parvovirus) and bacterial infection. Two-dimensional echocardiography confirmed atrial septal defect and pulmonary hypertension. Abdominal ultrasound scan revealed ascites, but no hepatomegaly or splenomegaly.

Because of high ventilatory requirements, he was switched from conventional mechanical ventilation to high-frequency oscillation. He had profound oxygenation failure (oxygenation index 63) and received inhaled nitric oxide therapy for persistent pulmonary hypertension, narrowly averting extracorporeal membrane oxygenation. He was extubated on day 14 to non-invasive positive pressure ventilation. From day 21, he was placed on heated humidified high flow nasal cannula at 30% oxygen. He had been kept nil by mouth and received standard total parenteral nutrition (TPN) since birth. Nasogastric tube feeding with an exclusive medium-chain triglyceride (MCT) formula (Monogen, Nutricia, North America) was started from day 14 and gradually increased till he took full feeds by day 19 of life. He regained birth weight by day 25 of life. Facial and limb oedema improved over the month.

In the second month of life, he continued to require respiratory support through high-flow nasal cannula at 5 L/min and 30% oxygen. Repeat echocardiography done at 33 days of life showed the pulmonary hypertension had resolved. High-resolution CT (HRCT) scan of the thorax performed at 44 days of life revealed the presence of diffuse ground-glass opacities in both lungs with sparing of the right middle lobe, consistent with diffuse interstitial lung disease (figure 2).

Figure 2.

Coronal (A, B) and axial (D, E) lung window images of the high-resolution CT scans obtained on day 25 of life demonstrate diffuse ground-glass/increased attenuation of the both lung parenchyma with partial sparing of the middle lobe (arrows in images A, E). Coronal (C) and axial (F) soft tissue window images of the chest also demonstrate mild thickening and increased attenuation/oedema of the intermuscular fat planes, likely related to known hydrops fetalis (white arrows).

Table 1.

List of investigations to evaluate hydrops fetalis and persistent oxygen dependency

Test	Results		Comments
Full blood count	Haemoglobin	17 g/dL	Normal
	Total white cell count	10.89×109/L
	Platelets	293×109/L
	Reticulocytes	5.43%
	Neutrophils	34%
	Lymphocytes	41%
	Monocytes	11%
	Basophils	1%
	Eosinophils	2%
Pleural fluid analysis	White cell count	0.1113 x 10ˆ9 cells/L	Characteristics of chylothorax1 4 6 42 Absolute cell count >1000 cell/uL Lymphocyte count >80% Proteins 2–6 g/dL pH 7.4–7.8 Milky (or clear, if unfed) Sterile Triglycerides >1.1 mmol/L Presence of chylomicrons Usually exudative but may be transudative
	Lymphocyte count	97%
	Lactate dehydrogenase	149 U/L (222–454)
	Triglyceride	0.24 mmol/L
	Protein	<30 g/L
Liver function test	Protein	47 g/L	Normal
	Albumin	31 g/L
	Bilirubin	34 μmol/L
	Alkaline phosphatase	103 U/L
	Alanine transaminase	5 U/L
	Aspartate transaminase	29 UL
	Lactate dehydrogenase	710 U/L
Renal panel	Urea	8.3 µmol/L	Normal
	Sodium	140 mEq/L
	Potassium	3.3 mEq/L
	Chloride	112 mEq/L
	Bicarbonate	22 mEq/L
	Creatinine	34 µmol/L
Peripheral blood karyotype	46XY		Normal male karyotype
Two-dimensional echocardiography	Moderate patent ductus arteriosus 3.1 mm with bidirectional flow across it. Left aortic arch with no coarctation. Normal pulmonary vein, no superior vena cava obstruction. Moderate atrial septal defect 5.4 mm with left-to-right flow across it. Pulmonary hypertension.		Atrial septal defect with pulmonary hypertension
High-resolution CT of the thorax (figure 2)	Normal cardiomediastinal structures. Normal trachea and airways with no defect. No confluent consolidation or discrete mass is seen in both lungs. Subtle diffuse ground-glass opacity in both lung parenchyma with sparing of middle lobe segments. Small patchy lucent foci scattered in bibasal dependent areas may represent mild degree of centrilobular air trapping. No obvious reticular septal thickening or effusion.		Diffuse interstitial lung disease, sparing the middle lobe

Differential diagnosis

The diagnosis of hydrops fetalis in the neonate reported here, was based on the presence of fluid collection in two or more organ systems—skin lymphoedema and pleural effusion. The cause for hydrops was not secondary to anaemia since haemoglobin level was normal at birth. A thorough search for other underlying aetiologies did not reveal congenital cardiac disorder, karyotype abnormality, metabolic disorder, bacterial or intrauterine infection. Pleural fluid analysis revealed that the neonate had congenital chylothorax, based on white cell count >1 x 10ˆ⁹ cells/L consisting of >80% lymphocytes.^{1 5 6} His pleural fluid appeared clear and straw-coloured at birth because he had not been fed¹ and would have been expected to turn milky or opalescent with the introduction of milk feeding. In order to evaluate the cause for his persistent respiratory distress and failure to wean respiratory support at 6 weeks of life, he underwent HRCT of the thorax, which revealed diffuse interstitial lung disease^{9 10} sparing the middle lobe.

The presentation of non-immune hydrops secondary to congenital chylothorax, in association with HRCT appearance of diffuse interstitial lung disease, led to suspicion of a lymphatic malformation. Further investigations to define the pathological abnormality and delineate the lymphatic drainage system were discussed in a multidisciplinary meeting when he was 3.5 months of life. Members comprising specialists from neonatology, pulmonology, haematology, interventional radiology and thoracic surgery discussed and agreed that the combination of congenital bilateral chylothorax at birth with a diffuse interstitial lung disease on HRCT scan made CPL the most likely diagnosis.

The advantages and challenges of undertaking further investigations were considered. Open lung biopsy had been reported to be clinically useful in eight neonates with respiratory failure who were awaiting or undergoing extracorporeal membrane oxygenation because it enabled clinicians to confirm a fatal lung dysplasia, irreversible lung pathology (such as pulmonary hypoplasia) or CPL.¹¹ Indeed, open lung biopsy remains the gold standard for diagnosis of CPL by revealing the presence of thin-walled lymphatic vessels devoid of smooth muscle, but with dilated lumen and lined by flattened endothelial cells.¹¹ It also provides definitive diagnosis in cases of interstitial lung disease of uncertain aetiology.⁷ However, the major risk of open lung biopsy in infancy is the requirement for general anaesthesia and postoperative bleeding (although small), while the area of interest may possibly be missed at sampling.

Lymphangiography^12–14 was proposed to visualise the lymphatic system as a less invasive modality of investigation than open lung biopsy. Fluoroscopic intranodal lymphangiography with injection of oil-based contrast material into the groin lymph nodes can improve the visualisation of central conducting lymphatic channels compared with the traditional methods, but is seldom practiced because of the risk of ionising radiation and potential for embolisation. Gadolinium-based contrast material injected into the groin lymph nodes for magnetic resonance lymphangiography had been reported more recently, but is technically challenging and time consuming in a small infant, because of dilution of contrast material by intestinal and hepatic non-opacified lymph flow.¹⁵ Lymphatic radionuclide scintigraphy¹⁶ was also considered, but would not be sensitive enough to detect abnormalities in such a small infant.

Balanced against the above modes of investigation (open lung biopsy, lymphangiography and lymphatic scintigraphy) with their inherent risks, the team next studied past reports of the disease trajectory of CPL to see if supportive management would be feasible and safe. At the time of the multidisciplinary meeting, the infant had remained stable on high-flow nasal cannula with no recurrence of effusion and was beginning to gain weight. The team thus decided that it would be prudent to monitor his respiratory status closely while allowing him to continue taking an exclusive diet of MCT formula. In a worst case scenario where he develops increasing respiratory symptoms and has recurrent effusions, or where histological diagnosis becomes imperative prior to instituting specific treatment, the team agreed by consensus that open lung biopsy, lymphangiography and lymphatic scintigraphy would be offered to the family. Both parents understood the rationale of an expectant approach and agreed with the team to adopt this wait-and-see plan with a view to carry out further investigation if necessary.

Treatment

Following HRCT scan, the infant continued to display persisting respiratory distress (tachypnoea, retractions) and required high-flow nasal cannula oxygen of 30% at 5 L/min to maintain oxygen saturations above 93% at 45 days of life. He received a 10-day course of intravenous dexamethasone (0.15 mg/kg/day for 3 days, 0.10 mg/kg/day for 3 days, 0.05 mg/kg/day for 2 days, and 0.02 mg/kg/day for 2 days; total of 0.89 mg/kg over 10 days)¹⁷ from day 47 of life for chronic lung disease, which facilitated weaning of respiratory support from 5 to 2 L/min. He was discharged home on day 88 (at a postconceptional age 2 months) with supplemental home oxygen therapy at 0.5 L/min, which was eventually weaned off a month later.

Outcome and follow-up

During outpatient follow-up, the infant initially had faltering growth, with weight declining to the 10th centile by 4 months. He had been fed an exclusive diet of MCT formula since he was 14 days old. A complementary diet was introduced early at 4 months of life, consisting of rice cereals once daily and gradually increasing to two times per day. He gained much better weight thereafter and crossed centile curves to reach the 25th–50th centile for weight and height by 6.5 months of life. At 6 months of life, after a prechallenge chest X-ray showed no recurrence of effusion (figure 3), he was challenged with expressed breast milk and successfully tolerated the switch from MCT formula to his mother’s own milk and eventually regular formula.

Figure 3.

Chest X-ray of the infant prior to human milk challenge showed no recurrence of effusion.

He received routine vaccinations against hepatitis B, diphtheria, tetanus, pertussis, poliomyelitis, Haemophilus influenzae, as well as palivizumab prophylaxis against respiratory syncytial virus. He developed one episode of parainfluenza bronchiolitis at 9.5 months of life, from which he recovered uneventfully. He continued to gain good weight and attained normal developmental milestones at 12 months of life. He remained stable with no respiratory exacerbations or need for supplemental oxygen.

Discussion

The neonate described here presented with typical features of bilateral congenital chylothorax. He developed severe respiratory failure and required emergency resuscitation, pleural drainage, high-frequency oscillation ventilation as well as inhaled nitric oxide therapy for persistent pulmonary hypertension. He narrowly averted extracorporeal membrane oxygenation for which he would have satisfied enrolment based on the very high oxygenation index. Our patient did not require pleurodesis nor octreotide. Several case reports have shown that in patients with congenital chylothorax that failed to resolve despite thoracocentesis, octreotide can reduce daily pleural drainage volumes.^{18 19} Octreotide acts directly on vascular somatostatin receptors to minimise lymphatic secretion and increase splanchnic arteriolar resistance with decreased gastrointestinal blood flow. However, octreotide may be associated with side effects of vomiting, diarrhoea, hyperglycaemia, hypotension and necrotising enterocolitis in preterm infants.²⁰

Since the infant continued to require support through high-flow nasal cannula at 5 L/min in 30% oxygen throughout the second month of life up to term (41 weeks) postmenstrual age, HRCT of the thorax was arranged to evaluate the pleural and pulmonary structures. HRCT revealed the presence of diffuse interstitial lung disease sparing the middle lobe. Faced with difficulty in weaning respiratory support, a trial of systemic steroids was commenced in the belief that he had severe chronic lung disease based on National Institute of Child Health and Human Development criteria.²¹ His positive improvement to systemic steroids provides evidence for the central role of inflammation in the pathogenesis of chronic lung disease.¹⁷ Yet, the appearance of diffuse interstitial lung disease on HRCT could not be explained solely by chronic lung disease, which would have been expected to affect all areas equally without sparing a particular lung lobe.^{9 10} We thus inferred that he might have had an underlying diffuse interstitial lung disease, but developed a superimposed chronic lung disease secondary to barotrauma in the first 2 weeks of life. More trials will be required in future to evaluate the effects of systemic steroids on neonates who undergo prolonged ventilation for congenital chylothorax, but do not develop chronic lung disease.²²

The multispecialist team managing the infant were faced with several dilemmas, one of which was the need to confirm a histopathological diagnosis and delineate the lymphatic drainage system in view of the presentation of bilateral chylothorax. There are currently no established guidelines recommending the extent of investigations for infants with congenital chylothorax and the order in which they should be carried out.

Literature review showed that reports consisted of individual cases or series with small numbers having undergone open lung biopsy, lymphangiography or lymphatic scintigraphy for diagnostic purposes.18 19 23–33 Interestingly, in the largest series of 63 cases of primary congenital chylothorax from China,²³ 12 were diagnosed with interstitial lung disease based on CT, similar to our patient. Among the 12 cases, 1 had histologically confirmed diffuse pulmonary lymphangiomatosis while 6 had a generalised lymphatic anomaly. We postulate that both chylothorax and interstitial lung disease are part of a spectrum of underlying lymphatic disorders, which include lymphangiomatosis,³⁴ lymphangiectasia^35–37 and atresia of the thoracic duct. In terms of the order of investigation, much of the choice would depend on the specific objective of the investigation, technical difficulty and inherent risks in performing it^11–16 and which explains why they are not often carried out.

Contrary to other case series^{38 39} with dismal survival rates in CPL, Barker et al⁴⁰ reported that eight of nine patients in his series survived and even improved over time. While we were aware that a confirmatory diagnosis of CPL can only be made in our patient by invasive testing through open lung biopsy, lymphangiography and lymphatic scintigraphy, we agreed to undertake a supportive and non-invasive approach based on the possibility of spontaneous resolution as described by Barker et al.⁴⁰

The initial dietary management of all infants with congenital chylothorax is an exclusive MCT-based formula because MCT is directly absorbed into the portal circulation, bypassing lymphatic channels. A second dilemma for the managing team is related to the duration of MCT formula to be given, as well as the composition of a complementary diet that should be introduced at 6 months of life in accordance with WHO recommendation.⁴¹ We recommended a dietary challenge with small amounts of his mother’s own milk containing long-chain fatty acids (LCFA) at 6 months of life. There are no guidelines regarding the rate of introduction of a LCFA-rich weaning diet to avoid overwhelming a potentially anomalous lymphatic system. One report revealed that a breast milk challenge in an infant with congenital chylothorax who had previously improved while taking an MCT-based formula, led to the recurrence of chylothorax.³¹ Indeed, it had been suggested that conservative management with a combination of TPN and MCT-based diet had been successfully in 80% of cases and averted the need for surgical intervention, such as thoracic duct ligation.²⁴

The growth and clinical course of our patient appeared similar to the patients with CPL reported by Barker et al.⁴⁰ He had faltering growth with weight gain decreasing from the 50th to 10th centile over the initial 2 months. The improved catch-up growth after 4 months of life was likely due to better nutritional intake.

In conclusion, the case reported here shows that in a neonatal patient with congenital chylothorax and HRCT finding of interstitial lung disease, it is prudent to adopt an expectant approach of watchful monitoring while continuing to provide a diet of exclusive MCT formula, followed by gradual introduction of a LCFA-rich diet during the weaning period. Long-term follow-up of his growth and development through the preschool years to adolescence will be required.

Learning points.

• Congenital chylothorax is the most common cause of neonatal pleural effusion and can be complicated by non-immune hydrops fetalis.

• When congenital chylothorax occurs in association with diffuse interstitial lung disease, congenital pulmonary lymphatic anomalies should be considered. Our patient potentially adds to a growing body of evidence that cases of congenital pulmonary lymphangiectasia do not necessarily face a dismal prognosis with timely and appropriate intervention.

• An exclusive medium-chain triglyceride formula is the standard of care in dietary treatment for neonatal chylothorax and may avert use of other treatment modalities, including octreotide, pleurodesis and thoracic surgery.

• Babies with congenital chylothorax or pulmonary lymphangiectasia often meet clinical criteria for chronic lung disease due to need for prolonged oxygen therapy and may respond to systemic corticosteroids.

• In complex cases of neonatal chylothorax with diffuse interstitial lung disease that develop chronic lung disease, it is imperative to discuss within a multidisciplinary specialist team so as to develop a management approach tailored to the needs of the individual patient.