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.