Efficacy of T cell assays for the diagnosis of primary defects in cytotoxic lymphocyte exocytosis.

Primary hemophagocytic lymphohistiocytosis (HLH) is a life-threatening disorder associated with autosomal recessive variants in genes required for perforin-mediated lymphocyte cytotoxicity. A rapid diagnosis is crucial for successful treatment. Although defective cytotoxic T lymphocyte (CTL) function causes pathogenesis, quantification of natural killer (NK) cell exocytosis triggered by K562 target cells currently represents a standard diagnostic procedure for primary HLH. We have prospectively evaluated different lymphocyte exocytosis assays in 213 patients referred for evaluation for suspected HLH and related hyperinflammatory syndromes. A total of 138 patients received a molecular diagnosis consistent with primary HLH. Compared to routine K562 cell-based assays, assessment of Fc receptor-triggered NK-cell and T cell receptor-triggered CTL exocytosis displayed higher sensitivity and improved specificity for the diagnosis of primary HLH, with these assays combined providing a sensitivity of 100% and specificity of 98.3%. By comparison, NK-cell exocytosis following K562 target cell stimulation displayed a higher inter-individual variability, in part explained by differences in NK-cell differentiation or large functional reductions following shipment. We thus recommend combined analysis of T cell receptor-triggered CTL and Fc receptor-triggered NK-cell exocytosis for the diagnosis of patients with suspected familial HLH or atypical manifestations of congenital defects in lymphocyte exocytosis.

Evaluation of Peripheral Lymphadenopathies in Children in a Single Center: Predictive Factors for Malignancy.

BACKGROUND: Lymphadenopathy (LAP) is a common finding in pediatric patients. It was aimed to determine predictive factors in distinguishing cases with malignant or benign lymphadenopathy in this study. SUBJECTS AND METHODS: Between January 2022 and January 2023, 101 patients (1-16 years old) with lymphadenopathy were retrospectively examined. RESULTS: LAP was localized in 80.2% (n=81) cases and generalized in 19.8% (n=20) cases. In 60 cases (59.4%), lymph node sizes were found to be greater than 20×20 mm in width and length. The most common infectious causative agent was Epstein Barr Virus (EBV). Seven (6.9%) patients underwent biopsy and all were diagnosed with malignancy. When the benign and malignant groups were compared, age, lymph node length, and width on physical examination, anteroposterior and longitudinal diameter of the lymph node on ultrasonography (USG) were statistically significantly higher in the malignant group (p<0.05). The presence of supraclavicular lymphadenopathy was found to be an important factor in differentiating the malignant group (p<0.003). The most important factors in distinguishing the groups are respectively were the anteroposterior diameter of the lymph node on ultrasonography and the presence supraclavicular lymph node in multivariate logistic regression analysis. CONCLUSION: It is not always easy to distinguish benign and malignant etiologies in patients with lymphadenopathy. A detailed history, a careful physical examination, laboratory studies, and excisional biopsy are guiding.

Coagulopathy is Initiated with Endothelial Dysfunction and Disrupted Fibrinolysis in Patients with COVID-19 Disease.

A substantial group of patients suffer from Covid-19 (CAC) coagulopathy and are presented with thrombosis. The pathogenesis involved in CAC is not fully understood. We evaluated the hemostatic and inflammatory parameters of 51 hospitalized Covid-19 adult patients and 21 controls. The parameters analyzed were danger signal molecule (High molecular weight group box protein-1/HMGBP-1), platelet count, prothrombin time (PT), activated partial thromboplastin time (aPTT), D-dimer, fibrinogen, endothelial protein C receptor (EPCR), soluble E-selectin, soluble P-selectin, thrombomodulin, tissue plasminogen activator (TPA), plasminogen activator inhibitor-1 (PAI-1), soluble fibrin monomer complex (SFMC), platelet-derived microparticles (PDMP), ß-thromboglobulin, antithrombin and protein C. The main objective of our study was to investigate which part of the hemostatic system was mostly affected at the admission of Covid-19 patients and whether these parameters could differentiate intensive care unit (ICU) and non-ICU patients. In this prospective case-control study, 51 patients ≥ 18 years who are hospitalized with the diagnosis of Covid-19 and 21 healthy control subjects were included. We divided the patients into two groups according to their medical progress, either in ICU or non-ICU group. Regarding the outcome, patients were again categorized as a survivor and non-survivor groups. Blood samples were collected from patients at admission at the time of hospitalization before the administration of any treatment for Covid-19. The analyzes of the study were made with the IBM SPSS V22 program. p < 0.05 was considered statistically significant. A total of 51 adult patients (F/M: 24/27) (13 ICU and 38 non-ICU) were included in the study cohort. The mean age of the patients was 68.1 ± 14.4 years. The control group consisted of 21 age and sex-matched healthy individuals. All of the patients were hospitalized. In a group of 13 patients, Covid-19 progressed to a severe form, and were hospitalized in ICU. We found out that the levels of fibrinogen, prothrombin time (PT), endothelial protein-C receptor (EPCR), D-dimer, soluble E-selectin, soluble P-selectin, plasminogen activator inhibitor-1 (PAI-1), and tissue plasminogen activator (TPA) were increased; whereas, the levels of soluble fibrin monomer complex (SFMC), platelet-derived microparticles (PDMP), antithrombin and protein-C were decreased in Covid-19 patients compared to the control group at hospital admission. Tissue plasminogen activator was the only marker with a significantly different median level between ICU and non-ICU groups (p < 0.001). In accordance with the previous literature, we showed that Covid-19 associated coagulopathy is distinct from sepsis-induced DIC with prominent early endothelial involvement and fibrinolytic shut-down. Reconstruction of endothelial function at early stages of infection may protect patients from progressing to ICU hospitalization. We believe that after considering the patient's bleeding risk, early administration of LMWH therapy for Covid-19, even in an outpatient setting, may be helpful both for restoring endothelial function and anticoagulation. The intensity of anticoagulation in non-ICU and ICU Covid-19 patients should be clarified with further studies. Supplementary Information: The online version contains supplementary material available at 10.1007/s12291-023-01118-3.

Castleman Disease: A Multicenter Case Series from Turkey

Objective: Castleman disease (CD) is a rare disease also known as angiofollicular lymph node hyperplasia. The two main histological subtypes are the hyaline vascular and plasma cell variants. It is further classified as unicentric CD (UCD) or multicentric CD (MCD) according to the anatomical distribution of the disease and the number of lymph nodes involved. The aim of this multicenter study was to evaluate all cases of CD identified to date in Turkey to set up a national registry to improve the early recognition, treatment, and follow-up of CD. Materials and Methods: Both adult (n=130) and pediatric (n=10) patients with lymph node or involved field biopsy results reported as CD were included in the study. Patients' demographic information, clinical and laboratory characteristics, imaging study results, treatment strategies, and clinical outcomes were evaluated retrospectively. Results: A total of 140 patients (69 male and 71 female) with a diagnosis of UCD (n=73) or MCD (n=67) were included. The mean age was 39 years in the UCD group and 47 years in the MCD group. Female patients were more common in the UCD group. The most common histological subtype was hyaline vascular for both UCD and MCD patients. Asymptomatic patients were more common in the UCD group. Anemia, elevations of acute phase reactants, and hypoalbuminemia were more common in the MCD group. The most commonly used treatment strategies for UCD were surgical excision, rituximab, and radiotherapy, respectively. All UCD patients were alive at a median of 19.5 months of follow-up. The most commonly used treatment strategies for MCD were methyl prednisolone, R-CHOP, R-CVP, and rituximab. Thirteen MCD patients had died at a median of 34 months of follow-up. Conclusion: This study is important in presenting the patient characteristics and treatment strategies for CD from Turkey, with the potential of increasing awareness about CD. Treatment data may help in making decisions, particularly in countries that do not have access to siltuximab. However, larger prospective studies are needed to make definitive conclusions.

Sublingual methylcobalamin treatment is as effective as intramuscular and peroral cyanocobalamin in children age 0-3 years.

PURPOSE: Vitamin B12 deficiency is a cause of preventable growth and developmental retardation in children. In this respect, alternative methods such as oral and sublingual treatments are being tried. We aimed to compare the efficacy of oral, sublingual, and intramuscular vitamin B12 treatments in children aged 0-3 years. METHODS: The study included 158 patients with serum vitamin B12 deficiency (serum vitamin B12 level <300 ng/L) aged 0-3 years retrospectively. According to the vitamin B12 treatment modalities, the patients were divided into three groups as oral cyanocobalamin (group 1), sublingual methylcobalamin (group 2), and intramuscular cyanocobalamin (group 3). RESULTS: The mean values of vitamin B12 levels increased to above 300 ng/L in all three groups. This increase was statistically significant for Group 1,2 and 3 (p<0.05). CONCLUSION: Sublingual methylcobalamin was determined as effective as oral and intramuscular cyanocobalamin improving vitamin B12 levels aged 0-3 years.What's already known about this topic?It is already known that intramuscular and oral cyanocobalamin treatments are effective in vitamin B12 deficiency of children.What does this article add?Sublingual methylcobalamin treatment, which is a new treatment method, was found to be as effective as oral and intramuscular cyanocobalamin treatments. To our knowledge, there is no study about sublingual treatment in children and comparing oral cyanocobalamin, intramuscular cyanocobalamin, sublingual methylcobalamin.

Persistent Hyperinsulinemic Hypoglycemia with Pancreatic Teratoma in Infancy: A Case Report.

BACKGROUND Pediatric intraabdominal pancreatic teratomas have been rarely reported. This is the first case of severe hyperinsulinemic hypoglycemia in a 6-month-old infant secondary to an intraabdominal teratoma. The hypoglycemia resolved after surgical removal. CASE REPORT A 6-month-old infant was seen in a pediatric emergency department with complaints of lethargy and abnormal eye movements. She was diagnosed with hyperinsulinemic hypoglycemia and started on diazoxide. A CT and MRI of the abdomen revealed a 165×77×72 mm cyst with a 51×45×30 mm solid structure connecting to the wall of the cyst by a stalk, raising suspicion of a fetus in fetu. The mass had no connection to her pancreas. Following total excision of the intraabdominal mass, her hypoglycemia resolved. Histopathological examination showed immature fetal pancreatic tissue consistent with a mature teratoma. Whole exon sequencing of the infant's peripheral blood showed a negative mutation of ABCC8 and presence of heterozygous variations of HNF1ß and IRS1 genes. CONCLUSIONS This is the first case report of an infant with severe hyperinsulinemic hypoglycemia secondary to a pancreatic teratoma. The heterozygous variations of HNF1ß and IRS1 genes likely played a role in the embryogenesis, causing a pancreatic teratoma and hyperinsulinemic hypoglycemia.