Discussion
PLFD involves abnormal lymphatic flow via the lymphatic channels to the lungs and pleural space; this disorder has been described as pulmonary lymphatic perfusion syndrome (PLPS) 4. PLFD commonly occurs in children with congenital heart disease and primary lymphatic dysplasia, including diffuse pulmonary lymphangiomatosis, primary pulmonary lymphangiectasis, and lymphatic dysplasia syndrome (i.e., YNS, Noonan syndrome). The main complication of PLFD is chylothorax; more rarely, accompanied by lymphatic PB. This study describes two cases of primary PLFD presenting as PB in the absence of chylothorax.
YNS is a rare disorder characterized by thickened yellow nails, primary lymphedema, and respiratory manifestations. The etiology of YNS remains unclear; however, a unifying lymphatic mechanism characterized by anatomical and/or functional lymphatic drainage abnormalities has been proposed 5-6. The main respiratory system manifestations are bronchiectasis and pleural effusion, and about 20% of the pleural effusion cases are chylothorax 7-8. In the current study, patient 1 presented with a chronic cough and expectoration of milky-white mucous plugs resembling bronchial casts, but without pleural effusion and lymphedema. The nail changes on the first toe had been interpreted as onychomycosis and had been removed before admission. Thus, the consideration of chyloptysis and YNS are challenging, resulting in a long diagnosis delay. To our knowledge, this is the first report of YNS presenting as lymphatic PB which further supports a lymphatic mechanism of YNS. The age at onset of patient 2 was early infancy; she had normal development and no history of other diseases, suggesting congenital lymphatic dysplasia. Diagnostic pulmonary biopsy was not performed because of the risk of massive chyloptysis or refractory chylothorax 9-10.
The clinical symptoms of lymphocytic PB are nonspecific and vary from case to case. Productive cough, wheezing, shortness of breath, and dyspnea are the most common manifestations and may be misdiagnosed as asthma, recurrent pneumonia, or other respiratory diseases. In the current study, patient 1 has been diagnosed with asthma and recurrent pneumonia, but inhaled corticosteroids and bronchodilators, as well as anti-infection therapy, failed to control the symptoms. ABPM was aslo suspected in patient 1; however, oral corticosteroids combined with antifungal treatment were ineffective. Patient 2 had been misdiagnosed as severe pneumonia. The casts produced by patient 1 and patient 2 were large, highly branched, and had multi-antennary structures; while the smaller and simpler structures with fewer branches are always seen in nonlymphocytic casts3.
The chest CT findings, even if non-specific, were highly suggestive of PLFD. The typical findings include smooth thickening of the interlobular septa and bronchovascular bundles, patchy ground-glass opacities, mediastinal and hilar masses, as well as pleural effusions11-12. Our two cases both had features suggestive of PLFD. Pulmonary lymphatic flow disorder was demonstrated by lymphoscintigraphy in both children. Lymphoscintigraphy has been widely considered as the main investigation to establish a diagnosis of lymphatic flow disorder; it has a high sensitivity of about 95%, a specificity of 100%, and can be used to visualize the functional status of the lymphatic system 13-14.
Due to the rarity of PLFD, there are no standardized treatment protocols. Dietary treatments, such as total low-fat and high MCT diets, have generally proven to be minimally effective. Systemic glucocorticoids, recombinant interferon, and chemotherapeutic agents have been tried with variable outcomes; these treatments are largely limited by their toxicity 15. Recently, treatments with the mTOR inhibitor sirolimus have been shown to be effective in patients with lymphatic malformations and those with vascular malformations with a lymphatic component, with good tolerability and few side effects16-17. In the current study, patient 2 received diet and sirolimus treatment only for one month and exhibited gradual improvement in her symptoms, thus the efficacy of these treatments could not be fully evaluated. It has been reported that percutaneous embolization of abnormal pulmonary lymphatic vessels in pediatric patients with a single-ventricle and in adult patients with PB results in alleviation of the symptoms 3, 18. However, the two children in the current study both had recurrence of casts after the lymphatic interventional procedure. Reasons for the recurrence might be associated with congenital lymphodysplasia, abnormal generation and proliferation of lymphatic vessels, and collateral development.
In conclusion, primary PLFD is a rare but important cause of PB in children. The clinical symptoms of lymphocytic PB are nonspecific; thus, the diagnosis may be long delayed, especially in the absence of chylothorax. Chest CT findings have highly suggestive significance for the diagnosis. Lymphatic interventional procedure may be effective for short-term resolution of the symptoms, but prone to recurrence.