Chylothorax as Rare Manifestation of Pleural Involvement in Waldenström Macroglobulinemia: Mechanisms and Management.

Here we report the clinical, pathological, and immunological features of a rare case of Waldenström macroglobulinemia (WM) with pleural infiltrations. An atypical chylothorax, successfully treated by videothoracoscopy, represented the main clinical feature of this case of low-grade lymphoplasmacytic lymphoma. Pleuropulmonary manifestations are rare (from 0 to 5% of cases) in WM, with chylothorax observed in just seven patients worldwide. In addition to describing this uncommon clinical presentation, we investigate hypothetical pathogenetic mechanisms causing chylothorax and through an up-todate review of available literature furnish helpful suggestions for diagnosis and management of chylothorax in WM patients.

Role of immunoglobulin supplementation for secondary immunodeficiency associated with chylothorax after pediatric cardiothoracic surgery.

OBJECTIVE: To evaluate whether intravenous immunoglobulin was linked to a reduction in sepsis in patients with prolonged chylothoraces postpediatric cardiothoracic surgery. DESIGN: Retrospective observational cohort study. SETTING: Tertiary pediatric cardiac surgical center. PATIENTS: Children with chylothoraces postcardiothoracic surgery from 1998 to 2006 divided into two groups: with and without intravenous immunoglobulin supplementation. INTERVENTION: Intravenous immunoglobulin supplementation. MEASUREMENTS AND MAIN RESULTS: Thirty-seven with chylothoraces (median duration 14 days; interquartile range, 10-32 and median maximum chyle drainage 1.9 mL/kg/hr; interquartile range, 1-3) were included, and 16 (43%) received intravenous immunoglobulin. The degree of lymphopenia was worse with longer duration of chylothorax (p = .005). There was a trend toward immunoglobulin depletion-IgG (p = .07) and IgM (p = .07) with higher volume chyle loss. Twenty-two of 37 (59%) developed bloodstream infection and 24 of 37 (65%) developed sepsis related to other organ systems. The rate of bloodstream infection and of sepsis in other organ systems was high at 25 (95% confidence interval 17-39) and 23 (95% confidence interval 15-34) episodes per 1,000 intensive care unit days, respectively. Intravenous immunoglobulin was not related to the bloodstream infection rate: adjusted hazard ratio 0.88 (95% confidence interval 0.20-3.94; p = .87) or rate of sepsis in other organ systems: hazard ratio 2.31 (95% confidence interval 0.21-24.29; p = .49) or the proportion surviving to hospital discharge (p = .37). CONCLUSION: Patients with prolonged, large-volume chyle loss had greater secondary immunodeficiency. Although the sample size was small and therefore able to detect only a large treatment effect from intravenous immunoglobulin, infectious outcomes were equal between the two groups.

Genome-wide gene expression analysis implicates the immune response and lymphangiogenesis in the pathogenesis of fetal chylothorax.

Fetal chylothorax (FC) is a rare condition characterized by lymphocyte-rich pleural effusion. Although its pathogenesis remains elusive, it may involve inflammation, since there are increased concentrations of proinflammatory mediators in pleural fluids. Only a few hereditary lymphedema-associated gene loci, e.g. VEGFR3, ITGA9 and PTPN11, were detected in human fetuses with this condition; these cases had a poorer prognosis, due to defective lymphangiogenesis. In the present study, genome-wide gene expression analysis was conducted, comparing pleural and ascitic fluids in three hydropic fetuses, one with and two without the ITGA9 mutation. One fetus (the index case), from a dizygotic pregnancy (the cotwin was unaffected), received antenatal OK-432 pleurodesis and survived beyond the neonatal stage, despite having the ITGA9 mutation. Genes and pathways involved in the immune response were universally up-regulated in fetal pleural fluids compared to those in ascitic fluids. Furthermore, genes involved in the lymphangiogenesis pathway were down-regulated in fetal pleural fluids (compared to ascitic fluid), but following OK-432 pleurodesis, they were up-regulated. Expression of ITGA9 was concordant with overall trends of lymphangiogenesis. In conclusion, we inferred that both the immune response and lymphangiogenesis were implicated in the pathogenesis of fetal chylothorax. Furthermore, genome-wide gene expression microarray analysis may facilitate personalized medicine by selecting the most appropriate treatment, according to the specific circumstances of the patient, for this rare, but heterogeneous disease.

Accumulation of CD8+CD45RA+CD62L+ T cells in acute chylothorax in neonates.

BACKGROUND: Acute chylothorax in neonates is a rare disease but results in significant loss of lymphatic cells. OBJECTIVES: The purpose of the study was to determine whether acute chylothorax in neonates results in quantitative changes of lymphocyte subpopulations in peripheral blood and chyle. METHODS: 6 neonates who had acute chylothorax after thoracic surgery due to transposition of the great arteries were prospectively enrolled in the study. Peripheral blood mononuclear cells (PBMC) and chylous fluid mononuclear cells (CFMC) including CD45RA+ and CD45RO+ T cells and the expression of the lymphocyte homing marker CD62L were investigated by fluorescence-activated cell sorting. RESULTS: In chyle, CD3+CD45RA+ T cells were significantly increased compared to peripheral blood (PMBC: median 65.8% of CD3+; range 32.3-76.9% vs. CFMC: 90.3%; 68.6-94.4%) (p = 0.02). In chyle, changes of percentages of the CD45RA+ were limited to CD8-expressing T cells (CD8+CD45RA+: PBMC: 77.3%; 69.3-85.6% vs. CFMC: 93.2%; 86.3-98.5%) (p = 0.02). The CD8+CD45RA+ were mainly CD62L+ (PBMC: 59.4%; 31.6-62.0% vs. CFMC: 87.8%; 62.7-90.7%) (p = 0.02). CONCLUSIONS: The study gives evidence that acute chylothorax in neonates results in immunophenotypic alterations and accumulation of certain T-cell subpopulations in the pleural cavity. Although limited by small numbers of patients due to the rare manifestation of the disease, we were able to demonstrate an abundance of CD8+CD45RA+ T cells expressing CD62L in the chyle compared to peripheral blood. However, whether CD62L expression may contribute to the accumulation of CD8+CD45RA+ T cells in chyle and whether quantitative changes of these specific cells are of clinical relevance has to be determined.

Immunologic status in pediatric cardiosurgical patients with chylothorax.

OBJECTIVE: The impact of lymphocyte and immunoglobulin loss on immunologic status has not been extensively studied in children with chylothorax. The purpose of this study was to evaluate immunologic profile of pediatric cardiosurgical patients who developed infection while suffering from prolonged postoperative chylothorax. METHODS: We retrospectively reviewed immunologic findings in 16 pediatric cardiac patients with post-operative chylothorax persisting ?7 days. Patients were on total parenteral nutrition, received colloides for replacement of chylous losses, and antibiotics and/or antimycotics for treatment of infection. Immunologic evaluation included immunoglobulin levels, cellular immunity, and phagocytic activity. For every parameter z-score was calculated according to age-dependent nomograms and t-test was used to compare z-score distribution with normal distribution. RESULTS: The immunoglobulin (IgG, IgM, and IgA) levels did not significantly differ from normal values, although 25% patients had IgG levels below normal range. The relative and absolute counts of peripheral blood lymphocytes were lower (p < 0.001) than normal values. Absolute numbers of blood B-lymphocytes (CD19+), T-lymphocytes (CD3+), helper/inducer T-cells (CD4+), and suppressor/cytotoxic T-cells (CD8+) were also below normal range (p < 0.001); however, their relative percentages and a CD4+/CD8+ ratio were within normal limits. The percentage and absolute number of natural killer cells (CD16+), phagocytic and metabolic activity of polymorphonuclear leukocytes did not differ from normal values. CONCLUSIONS: Persisting chylothorax results in B-cell and T-cell lymphopenia with proportional decline of CD4+ and CD8+ cells. Hypogammaglobulinemia observed in other studies has not been detected in this series probably due to administered plasma. Effects of these immunologic alterations on development of infection are unknown (Tab. 2, Ref. 13).

The lymphatics in the pathophysiology of thoracic and abdominal surgical pathology: immunological consequences and the unexpected role of microsurgery.

The authors report their experience in the diagnosis and treatment of lymphatic and chylous disorders in the thoracic and abdominal areas. Sixteen patients (10 adults, 6 children) affected by primary chylous ascites with associated syndromes and consequent immunological incompetence were studied. Diagnostic investigations included abdominal sonography scans, lymphoscintigraphy, and lymphography combined with computed tomography and laparoscopy. Surgical treatment included laparoscopy, drainage of ascites and/or the chylothorax, treatment of abdominal and retroperitoneal chylous leaks, exeresis of lymphodysplastic tissues, ligation of incompetent lymph vessels also by CO(2) LASER, and chylo-venous and lympho-venous microsurgical shunts. Eleven patients did not have a relapse of the ascites and four patients had a persistence of a small quantity of ascites with no protein imbalance. All patients had an improvement of their immunocompetence. Median follow-up was 5 years. We demonstrated that the use of microsurgery is remarkably advantageous for performing a causal treatment of the dysfunction.

Proinflammatory macrophage migratory inhibition factor and interleukin-6 are concentrated in pleural effusion of human fetuses with prenatal chylothorax.

OBJECTIVES: To study the role of selected cytokines and growth factors involved in the pathogenesis of fetal chylous pleural effusion. METHODS: Seventeen fetuses with prenatal chylothorax at gestational age (GA) 17-29 weeks were enrolled as the study group during the period 2003-2005. Their pleural effusion (n = 17) and amniotic fluid (n = 17) were drawn when disease set in. Eleven fetuses received cordocentesis because of suspected fetal anemia. Forty-one normal fetuses without adverse perinatal outcome at GA 17-29 weeks received amniocentesis and were enrolled in the reference group. Levels of hepatocyte growth factor (HGF), stromal-derived factor-1(SDF-1), vascular endothelial growth factor (VEGF), interleukin-8 (IL-8), macrophage migratory inhibition factor (MIF), and interleukin-6 (IL-6) were determined in the samples from both groups (amniotic fluid, pleural fluid, and cord blood from the study group and amniotic fluid from the reference group) by enzyme-linked immunoassay (EIA). RESULTS: No significant differences were observed in the amniotic fluids between the study group and the reference group regarding levels of IL-6, IL-8, MIF, SDF-1, HGF and VEGF. In the study group, levels of IL-8, VEGF and SDF-1 (all pro-angiogenic) showed no significant differences between the amniotic fluid, cord blood and pleural effusion. The level of HGF (proangiogenic) was significantly higher in the amniotic fluid than in the cord blood or the pleural effusion, but there were no significant differences between the levels in the pleural fluid and in the cord blood. Interestingly, the levels of MIF and IL-6 (both are proinflammatory) in the amniotic fluid and in the pleural effusion were much higher than the levels in the cord blood. CONCLUSION: Our study demonstrated that the levels of pro-inflammatory proteins (MIF and IL-6) that we tested were higher in the fetal pleural effusion than in the fetal circulation, a phenomenon not observed in the levels of proangiogenic proteins (HGF, SDF-1, VEGF, IL-8). This result implies that inflammation-related proteins may be more relevant than the angiogenesis-related proteins in the local environment of accumulating pleural effusion, a prominent feature of prenatal chylothorax.

Pleural fluid/serum immunoglobulin ratio is a diagnostic marker for congenital chylothorax in utero.

OBJECTIVE: To distinguish congenital chylothorax from other causes of hydrothorax in utero. METHODS: Serum and pleural fluid samples from 8 fetuses with congenital chylothorax and 5 control fetuses with other causes of hydrothorax were tested for total protein, albumin, IgG, IgA, and IgM. RESULTS: Fetuses with congenital chylothorax had higher levels of IgG in pleural fluid, but not the other four proteins, than control fetuses (P<0.05). There were no significant differences in serum proteins among fetuses. When we examined pleural fluid to serum ratios, the IgG ratio in fetuses with congenital chylothorax was significantly higher than that of control fetuses (P<0.05). The IgG ratio in chylothorax was greater than 0.6 regardless of lymphocyte count. CONCLUSION: Pleural fluid/serum IgG ratio may be a diagnostic marker for congenital chylothorax in utero.

Acute chylothorax in children: selective retention of memory T cells and natural killer cells.

OBJECTIVE: To assess for immunodeficiency in patients with hypogammaglobulinemia in the setting of draining acute chylothorax. STUDY DESIGN: Humoral and cellular immunity was evaluated in 8 patients with chylothorax. Chylous fluid was also analyzed to document cellular losses. Data regarding clinical course and immunologic characteristics were reviewed retrospectively. RESULTS: All patients had hypogammaglobulinemia (IgG=179+/-35 mg/dL) as well as lymphopenia (985+/-636 cells/mm(3)). T cells were decreased and natural killer cells increased in peripheral blood. The converse was found in chylous fluid. The ratio of CD3+/CD45RA+ naive: CD3+/CD45RO+ memory T cells was greater in chyle than in peripheral blood. In vitro proliferative responses to antigens and mitogens were similar to control subjects, and previously immunized patients maintained evidence of protective vaccine-specific humoral immunity. To treat hypogammaglobulinemia, patients received intravenous immunoglobulin (IVIG) to maintain IgG within normal range; 6 of 8 patients had serious infections before receiving IVIG compared with 4 of 8 patients during the period of IVIG administration. CONCLUSION: Draining chylothorax resulted in IgG and lymphocyte depletion with preferential retention of memory T cells and natural killer cells in the circulation. Overall, protective-specific antibody levels and T cell function were maintained. IVIG administration did not lead to discernible protection from infectious complications in this small group of patients.

Early complications. Chylothorax.

Postpneumonectomy chylothorax is a very common but serious complication. Drainage of the pneumonectomy space, metabolic and nutritional support with TPN, and absolute enteral rest may lead to control of the leak. Failure of these measures to obtain a rapid resolution of the chyle losses should be followed by early surgical intervention in most instances in an effort to alleviate the chronic metabolic, nutritional, and immunological consequences of prolonged chyle losses.

[The changes in lymphocytes subpopulations of a patient with postoperative chylothorax].

A case of 64-year-old male who developed chylorrhea at 2 days post coronary artery by-pass grafting, is reported. He was managed conservatively for 3 weeks. But chylothorax was not improved, he was treated operatively. Analysis of his lymphocyte subpopulations in peripheral blood were performed during the course of chylothorax. Lymphocytepenia became apparent and subpopulation of T cell were decreased gradually. The subpopulation of CD 4(+) cell decreased, while the subpopulation of CD 8(+) increased. The CD 4(+) cell/CD 8(+) cell ratio decreased consequently till 7th day after 2nd operation. Although the replenishment of nutritional deficiencies using TPN allows prolonged conservative management for chylothorax patient, the deterioration in cellular immunocompetence can not be prevented at present. It is necessary to take great care about infection for chylothorax patient.

Lymphocyte subpopulations in children with abnormal lymphatic circulation.

Peripheral blood lymphocyte subsets were enumerated in five children with abnormal lymphatic circulation (three with lymphangiectasia, one with chylothorax, and one child with chyloperitoneum). All patients were lymphopenic. The percentage and absolute number of blood T-lymphocytes (CD3) were low in two children and normal in the other children. The percentage and absolute number of helper/inducer lymphocytes (CD4) were markedly reduced in all patients. The percentage of suppressor/cytotoxic lymphocytes (CD8) was normal or elevated in all children, and the absolute number of CD8 cells was normal in three patients. The CD4/CD8 ratio was reversed in all patients. In the two patients tested, the proliferative response of peripheral blood mononuclear cells to mitogens was reduced. T-lymphocyte subsets were measured in the pleural or peritoneal fluid of three patients, and the CD4/CD8 ratio was normal or increased. In each child, the CD4/CD8 ratio in the lymphatic fluids was markedly higher than the CD4/CD8 ratio of the blood (4.0/0.45, 1.75/0.95, and 1.3/0.85). The reversed CD4/CD8 ratio in the blood in cases of chronic loss of chyle may be due to either selective transport of CD4 lymphocytes into the lymphatic fluids or a shorter half-life of CD8 compared to CD4 lymphocytes. This finding may in part explain the abnormal cellular immunity previously observed in patients with lymphangiectasia.