Neutrophil-to-Lymphocyte and Platelet-to-Lymphocyte Ratio in Univentricular Patients From Birth to Follow-Up After Fontan—Predicting Lymphatic Abnormalities

Background: Reliable laboratory parameters identifying complications after Fontan surgery including the lymphatic abnormalities and the development of protein-losing enteropathy (PLE) are rare. Neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocte ratio (PLR) are inflammatory markers and have been studied to predict outcome and prognosis in various diseases. The aim of this study was to investigate NLR and PLR from birth to follow-up after Fontan and evaluate their use as prognostic parameters for single ventricle patients regarding the development of lymphatic malformations during follow-up.Materials and Methods: Sixty-six univentricular patients who underwent Fontan surgery and had 6-month follow-up magnetic resonance imaging (MRI) with T2 weighted lymphatic imaging after total cavopulmonary connection (TCPC) surgery were included in the study. NLR and PLR were determined at specific time points, from neonatal age to follow-up after Fontan operation and correlated to data from the MRI 6 months after Fontan.Results: NLR and PLR increase significantly over time from the first surgery during infancy to the follow-up after Fontan (both p < 0.0001), with a significant increase after the Glenn surgery for both ratios (each p < 0.0001). Higher NLR (p = 0.002) and higher PLR (p = 0.004) correlated with higher-grade classification of lymphatic abnormalities in T2-weighted imaging 6 months after Fontan surgery and higher NLR correlated with higher transpulmonary gradient prior to Fontan surgery (p = 0.035) Both ratios showed a significant correlation to total protein at follow-up (NLR p = 0.0038; PLR<0.0001).Conclusion: Increased NLR and PLR correlate with higher degree lymphatic malformations after TCPC and therefore might contribute as valuable additional biomarker during follow-up after TCPC. NLR and PLR are simple, inexpensive and easily available parameters to complement diagnostics after TCPC.

Lymphatic Abnormalities in Noonan Syndrome Spectrum Disorders: A Systematic Review

Noonan syndrome spectrum disorders are a group of phenotypically related conditions, resembling Noonan syndrome, caused by germline pathogenic variants in genes within the Ras/mitogen-activated protein kinase (Ras/MAPK) signalling pathway. Lymphatic dysplasia with a clinical lymphatic abnormality is one of the major features. We performed a systematic review to get more insight in (1) the prevalence of clinically lymphatic abnormalities in patients with a genetically proven Noonan syndrome spectrum disorder, (2) if a genotype-lymphatic phenotype relation can be found and describe the clinical presentation and course of the lymphatic abnormality. Most studies report patients with Noonan syndrome. Prenatally, the prevalence of increased nuchal translucency differs from 7% in patients with pathogenic <i>PTPN11</i> variant<i>s</i> to 38% in patients with pathogenic <i>RIT1</i> variants, and the prevalence of pleural effusions differed from 7% in patients with pathogenic <i>SOS1</i> to 29% in patients with pathogenic <i>RIT1</i> variants. Postnatally, the prevalence of lymphedema differs from 16% in patients with pathogenic <i>PTPN11</i> variants to 44% in patients with pathogenic <i>SOS1</i> variants, and the prevalence of acquired chylothorax is 4% in patients with pathogenic <i>RIT1</i> variants. Lymphatic abnormalities do occur in patients with cardiofaciocutaneous syndrome and Costello syndrome. In conclusion, Noonan syndrome spectrum disorders, Noonan syndrome in particular, are associated with lymphatic abnormalities. Combining the available published literature about genetically proven Noonan syndrome spectrum disorders, it appears likely that the lifetime prevalence of these abnormalities in Noonan syndrome is higher than the 20% that were generally accepted so far. This is increasingly important, because the activation of the RAS/MAPK pathway can be inhibited by RAS/MAPK inhibitors, and clinically severe lymphatic abnormalities may improve.

68Ga-NOTA-Evans Blue PET/CT findings in lymphangioleiomyomatosis compared with 99mTC-ASC lymphoscintigraphy: a prospective study

Background Lymphangioleiomyomatosis (LAM) is a rare multisystem disease characterized by cystic lung disease and extrapulmonary manifestations, including lymphatic system disorder. The objective of this study was to investigate the findings of 68Ga-NOTA-Evans Blue (NEB) PET/CT in LAM and compare it with that of 99mTc-ASC lymphoscintigraphy. Methods Ten patients diagnosed with LAM according to the American Thoracic Society/Japanese Respiratory Society guidelines for LAM were recruited in this study. PET/CT acquisition was performed at 20 to 40 min after subcutaneous injection of 68Ga-NEB into the first interdigital spaces of both feet (0.3 ml, 37 MBq/foot). All subjects also underwent 99mTc-antimony sulfide colloid (ASC) lymphoscintigraphy within a week for comparison. Results 68Ga-NEB PET/CT displayed various lymphatic system abnormalities in 10 (100%) of 10 patients. These included pulmonary lymphatic abnormalities in 10 (100%) of 10 patients, enlarged lymph nodes in 5 (50%), lymphangioleiomyomas in 2 (20%), dilation of the lumbar trunk and/or iliac lymph vessels in 5 (50%), thoracic duct dilation in 2 (20%), chylous effusion in 1 (10%). For pulmonary lymphatic abnormalities, the positive rates of 68Ga-NEB PET/CT and 99mTc-ASC lymphoscintigraphy were 100% (10/10) and 10% (1/10), respectively (P < 0.001). As for the 7 patients with extrapulmonary lymphatic manifestations, 68Ga-NEB PET/CT also presented more information than 99mTc-ASC lymphoscintigraphy. Conclusion 68Ga-NEB PET/CT visualized pulmonary lymphatic abnormality and displayed extrapulmonary lymphatic system disorders of LAM, and might play a role in the diagnosis and evaluation of the disease. 68Ga-NEB PET/CT is advantageous over conventional 99mTc-ASC lymphoscintigraphy in LAM by providing more detailed information of lymphatic dysfunction.

Noonan Syndrome with Plastic Bronchitis in an Adult

Noonan syndrome is an autosomal dominant disease with low incidence. The incidence of Plastic bronchitis is not well defined. In Noonan syndrome, various lymphatic abnormalities have been described. Due to these abnormalities Plastic bronchitis may develop in the patients of Noonan syndrome.

EXPRESS: Magnetic Resonance Lymphangiography in Group 1 Paediatric Pulmonary Arterial Hypertension

Pulmonary hypertension could have thoracic lymphatic abnormalities caused by right ventricular failure. Since there is no description of such abnormalities, the purpose of this study was to investigate them with magnetic resonance. Prospective review magnetic resonance T2-weighted lymphangiography was performed between January 2017 and October 2019 through quantitative thoracic duct diameter, diameter index and qualitative lymphatic abnomalities types: 1- little or none abnormalities, 2-abnormalities in supraclavicular region, 3-abnormalities extending into the mediastinum, and 4-abnormalities extending into the lung. Five patients group 1 pulmonary arterial hypertension participated in this study. The mean: age was 12.44±4.92 years old, three male and two female, The quantitative analysis yielded the following results: mean thoracic duct diameter of 2.92±0.16 mm, and thoracic duct index 2.28±1.03 mm/m2. Qualitative lymphangiography abnormalities were type 1 in three patients, type 2 in one, all with low risk determinants and type 3 in one with hight risk determinants and rigth ventricular faillure. Magnetic resonance T2-weighted lymphangiography in group 1 paediatric pulmonary arterial hypertension allowed for the identification of the thoracic duct, wich was used to perform both quantitative and qualitative analysis of thoracic lymphatic abnormalities, in particular when increased high risk determinants and rigth ventricular faillure were present, These features represents an extracardiac findings useful to understand systemic venous congestion impact on lymphatic system.

NON-CONTRAST MR LYMPHOGRAPHY OF RARE LYMPHATIC ABNORMALITIES

Detailed imaging of the lymphatic system often requires direct injection of contrast into lymph nodes which can be technically challenging, time consuming, and produce painful stimuli. We sought to describe the use of non-contrast MR lymphography (NCMRL) for normal controls and patients with a variety of rare disorders associated with lymphatic pathologies. Two control subjects and five affected patients (decompensated Fontan circulation, central conducting lymphatic abnormality, familial lymphedema and two with Gorham-Stout disease) were studied. NCMRL images were segmented in a semi-automated fashion and the major lymphatic channels and thoracic duct (TD) highlighted for identification. Adequate imaging was available for both controls and 4/5 affected patients; the youngest patient could not be imaged given patient motion. For the two controls, the TD was seen in the expected anatomic location. For the decompensated Fontan patient, there were numerous tortuous lymphatic channels, predominantly in the upper chest and neck. For the familial lymphedema patient, a TD was not identified; instead, peripheral lymphatic collaterals near the lateral chest walls. For the first Gorham-Stout patient, the TD was enlarged with large intrathoracic lymph collections. For the second Gorham-Stout patient, there were bilateral TD with lymph collections in vertebral bodies. Using NCMRL, we were able to image normal and abnormal lymphatic systems. An important learning point is the potential need for sedation for younger patients due to long image acquisition times and fine resolution of the structures of interest.

Sphingolipid, fatty acid and phospholipid metabolites are associated with disease severity and mTOR inhibition in lymphangioleiomyomatosis

BackgroundLymphangioleiomyomatosis (LAM) is a rare multisystem disease almost exclusively affecting women which causes loss of lung function, lymphatic abnormalities and angiomyolipomas. LAM occurs sporadically and in people with tuberous sclerosis complex (TSC). Loss of TSC gene function leads to dysregulated mechanistic target of rapamycin (mTOR) signalling. As mTOR is a regulator of lipid and nucleotide synthesis, we hypothesised that the serum metabolome would be altered in LAM and related to disease severity and activity.MethodsUltrahigh performance liquid chromatography-tandem mass spectroscopy was used to examine the serum metabolome of 79 closely phenotyped women with LAM, including 29 receiving treatment with an mTOR inhibitor and 43 healthy control women.ResultsSphingolipid, fatty acid and phospholipid metabolites were associated with FEV1 in women with LAM (eg, behenoyl sphingomyelin adjusted (adj.) p=8.10 × 10-3). Those with higher disease-burden scores had abnormalities in fatty acid, phospholipid and lysolipids. Rate of loss of FEV1 was associated with differences in acyl-carnitine, acyl-glycines, acyl-glutamine, fatty acids, endocanbinoids and sphingolipids (eg, myristoleoylcarnitine adj. p=0.07). In TSC-LAM, rapamycin affected modules of interrelated metabolites which comprised linoleic acid, the tricarboxylic acid cycle, aminoacyl-tRNA biosynthesis, cysteine, methionine, arginine and proline metabolism. Metabolomic pathway analysis within modules reiterated the importance of glycerophospholipid metabolites (adj. p=0.047).ConclusionsWomen with LAM have altered lipid metabolism. The associations between these metabolites, multiple markers of disease activity and their potential biological roles in cell survival and signalling, suggest that lipid species may be both disease-relevant biomarkers and potential therapeutic targets for LAM.

Lymphatic Decompression Concomitant With Fontan/Kreutzer Procedure: Early Experience

Objective: To present a strategy for identifying patients at risk of lymphatic failure in the setting of planned Fontan/Kreutzer completion, allowing a tailored surgical approach. Methods: Since January 2017, clinical evaluation before performance of the Fontan/Kreutzer procedure included T2-weighted magnetic resonance imaging (MRI) lymphangiography. Thoracic lymphatic abnormalities were categorized using a scale of I to IV according to progression of severity. Patients with severe lymphatic abnormalities (types III and IV) underwent Fontan/Kreutzer with lymphatic decompression via connection of the left jugular–subclavian junction containing the thoracic duct to the systemic atrium (group A). Results: Thirteen patients were enrolled. Magnetic resonance imaging showed type I abnormalities in four cases (30.7%), II in four (30.7%), III in two (15.3%), and IV in three (23.3%). Patients in types III and IV underwent a Fontan/Kreutzer with lymphatic decompression (group A, n = 5), while patients in types I and II underwent a fenestrated extracardiac Fontan/Kreutzer procedure without lymphatic decompression (group B, n = 8). Preoperatively, there were no differences in age, weight, ventricular dominance (right vs left), superior vena cava pressure, incidence of chylothorax after previous superior cavopulmonary anastomosis (Glenn), or need for concomitant procedures at Fontan/Kreutzer completion. There were no differences in procedural times between the groups, nor were there differences in mortalities and Fontan/Kreutzer takedowns. There were no statistically significant differences in early and late morbidity between the two groups with the exception of total volume of effusions output postoperatively. At median follow-up of 18 months (range, 4-28 months), all patients in group A are in New York Heart Association class 1 with no differences between groups in arterial oxygen saturation. Conclusions: Lymphatic decompression during Fontan/Kreutzer procedure was successfully performed in patients identified by MRI as predisposed to lymphatic failure. A larger cohort of patients and longer follow-up are required to determine the efficacy of this approach in preventing early- and long-term Fontan/Kreutzer failure.