British Paediatric Orphan Lung Diseases (BPOLD)

Introduction
Lymphatic fluid in the lung is derived from normal leakage of fluid out of the blood capillaries in the lung and the intestines. In PL the channels (lymphatics) that carry lymph fluid are not properly connected and become dilated with fluid (lymphangiectasia). This fluid makes the lungs less elastic, which this causes breathing difficulties Mostly PL presents with severe respiratory distress in the newborn period, although later onset forms of PL have been described in a number of cases. The mortality of neonatal PL was previously reported to be nearly 100%. However, most of these reports were published nearly 30 years ago and neonatal care has advanced significantly since that time. Several recent case reports and case studies indicate that infants are now surviving the severe neonatal form of PL and the outcome is good for infants who present after the neonatal period. This report describes the latest concepts on what may cause this condition, its clinical presentation, how to make a diagnosis of PL, what successful strategies have been used to treat PL, and the outcome of PL.

Incidence
The overall incidence of pulmonary lymphangiectasia is unknown. Autopsy studies suggest that approximately 1% of infants who are stillborn or die in the neonatal period have pulmonary lymphangiectasia. Most case series have reported that more males than females are affected. In most cases, there is no familial pattern, and in some PL may occur together with a number of genetic syndromes including Noonan, Down, Turner, and Fryns, yellow nail syndrome and congenital icthyosis. Most of these syndromes are associated with generalized abnormalities of the lymphatic system.

Classification and Causes
Pulmonary lymphangiectasia is broadly divided into 2 categories: primary pulmonary lymphangiectasia where there is an intrinsic abnormality of the lymph channels, and secondary pulmonary lymphangiectasia, where the lymph channels are normal, but there is some downstream blockage to lymph flow.

Primary PL can be subdivided into generalized, pulmonary, and syndromic forms. The generalized form involves lymph vessel changes in many organ systems including the subcutaneous tissue, intestine, and lung. The major symptoms include generalized edema and protein loss from intestinal lymph vessels. Hemihypertrophy (enlargement of one limb) is common. Lung involvement in typically not severe, and survival in patients with pulmonary involvement is reported to be better than with the other forms of pulmonary lymphangiectasia. The primary pulmonary form of lymphangiectasia includes those patients with disease confined to the lung. This form is the classic congenital pulmonary lymphangiectasia previously described as having a very poor prognosis. In the syndromic form, PL is associated with multiple other unrelated congenital anomalies including the genetic syndromes mentioned earlier.
The cause of primary PL is not known. There is some evidence that the lung lymphatics are not properly “programmed” as they are developing in the fetus, so that the lymph systems in different parts of the lungs are never connected to the large channels that drain the fluid away. In some cases, there is evidence that the lymphatics may be normal at birth, and that subsequent abnormalities may result from a lung infection.

Secondary PL includes those forms that are due to downstream blockage of the lymphatics (e.g. surgery, trauma, lung disease) or congestion of the pulmonary veins, (usually from abnormal pulmonary veins on an abnormal heart).

Clinical Presentations
The clinical symptoms of pulmonary lymphangiectasia can present prenatally, at birth (neonatal) or after an asymptomatic period (post-neonatal). In the prenatal period, pulmonary lymphangiectasia can be a cause of swelling of the fetus (non-immune hydrops fetalis) and excess amniotic fluid (polyhydramnios), and fluid in the chest cavity (pleural effusions). Many infants are stillborn. The neonatal presentation manifests as respiratory distress at, or within a few hours of birth. Mechanical ventilation is often required. The post-neonatal presentation can occur after weeks or months of mild or absent respiratory symptoms. A few cases have presented for the first time in childhood or adolescence. Typical presenting symptoms include rapid breathing, and recurrent cough or wheeze. Examination of the patient usually reveals the presence of fine crackles throughout the lungs. Although pleural effusions are reported in up to 15% of patients. Pleural effusions typically contain lymph (cloudy) fluid, but may be clear, particularly if the newborn infant has not yet been fed.

Investigations
Diagnosis of pulmonary lymphangiectasia can be difficult, as many of the respiratory symptoms and radiological (X-rays, CT scan etc) findings are non-specific. Chest X-rays are usually abnormal, reflecting fluid in the chest cavity or lung tissue in infants, and overexpansion of the lungs in older infants and children. Chest computerized tomography (CT) scans of patients with pulmonary lymphangiectasia show patchy areas of fluid and over inflation of the lungs. Magnetic resonance imaging (MRI) may be used in the future for making a diagnosis of PL, but is not yet of proven value.
In many patients an open lung biopsy is helpful to distinguish pulmonary lymphangiectasia from other forms of lung disease. Care must be taken with the pathologic evaluation of the biopsy as the changes of pulmonary lymphangiectasia can be mistaken for interstitial emphysema or overlooked. Although dilated pleural lymphatics present a theoretical risk of chylothorax at the time of lung biopsy (leakage of lymph fluid from the incision site), this complication has not been reported .

In experienced hands, the diagnosis of PL can, in many cases, be made through a combination clinical and radiological evaluation, but a lung biopsy may be the only way to make the diagnosis of PL, particularly if there is concern that there may be another specific diagnosis (e.g. another type of interstitial lung disease).
Lung function studies show varying patterns of obstructive and restrictive disease with no deterioration over time. In infancy, patients present with recurrent with bronchitis, often caused by easily treatable pathogens including Streptococcus pneumonia and Moraxella cattharalis.

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Clinical Course
While there are undoubtedly infants whose PL is so severe that they cannot be saved, it is likely that many of the infants reported to have died previously with uncomplicated PL would have survived with current practices of neonatal intensive care. The oldest reported survivors in recent case series are 12 to 13 years old and are predicted to live into adulthood. Most patients who survive the neonatal and early infancy period continue to have respiratory problems (recurrent cough, wheeze and pneumonia) in the first several years of life with increased rates of hospitalization. A few patients require home supplemental oxygen for a period of time. Overall, respiratory condition and X-ray abnormalities improve during infancy and childhood, with many patients having minimal symptoms by age six. Of note, no deaths have occurred in the recent reported cohorts of patients who survived infancy.

Many patients with pulmonary lymphangiectasia who survive beyond infancy have other medical problems common to patients with chronic lung disease. Gastroesophageal reflux is frequent, poor growth is also not uncommon in the first few years of life, although most patients resume normal growth patterns by age 3 years. Both reflux and poor growth may be secondary to the increased work of breathing typical of patients with pulmonary lymphangiectasia rather than any specific abnormality.

Treatment
There is no specific treatment for PL. The main strategy is to support the patient by treating respiratory failure in the neonatal period and lung infections later on in the expectation that he condition will improve over time. Mechanical ventilation is often required in the neonatal form of PL, and specific strategies (e.g. pressure support with high mean airway pressures) have been successfully used as a strategy for neonatal respiratory failure. Some infants develop rapidly expanding pleural effusions that require placement of chest tube that may drain large volumes of fluid over days or weeks, but in most cases, this problem resolves over time. Other specific therapies including nutritional therapy with medium chain triglycerides and total parenteral nutrition have been successfully employed for treatment of chylothorax.

Conclusion:
Pulmonary lymphangiectasia can occur as a result of an intrinsic developmental anomaly, or from postnatal obstruction of pulmonary lymphatic or venous drainage. The timing and severity of the initial presentation is variable. Advances in neonatal care have significantly improved the outcome in even the most severe cases. PL can be diagnosed with a combination of clinical assessment, radiological studies and lung biopsy. Treatment is essentially supportive. The long-term outcome of PL is uncertain, but current evidence suggests that for the majority of patients with either neonatal or post-neonatal presentations, there is gradual improvement of clinical status over time, particularly if there are no significant co-existing abnormalities.