COVID-19 disease in children and adolescents following allogeneic hematopoietic stem cell transplantation: A report from the Turkish pediatric bone marrow transplantation study group.

BACKGROUND: Data on the risk factors and outcomes for pediatric patients with SARS-CoV-2 infection (COVID-19) following hematopoietic stem cell transplantation (HSCT) are limited. OBJECTIVES: The study aimed to analyze the clinical signs, risk factors, and outcomes for ICU admission and mortality in a large pediatric cohort who underwent allogeneic HSCT prior to COVID-19 infection. METHOD: In this nationwide study, we retrospectively reviewed the data of 184 pediatric HSCT recipients who had COVID-19 between March 2020 and August 2022. RESULTS: The median time from HSCT to COVID-19 infection was 209.0 days (IQR, 111.7-340.8; range, 0-3845 days). The most common clinical manifestation was fever (58.7%). While most patients (78.8%) had asymptomatic/mild disease, the disease severity was moderate in 9.2% and severe and critical in 4.4% and 7.6%, respectively. The overall mortality was 10.9% (n: 20). Deaths were attributable to COVID-19 in nine (4.9%) patients. Multivariate analysis revealed that lower respiratory tract disease (LRTD) (OR, 23.20, p: .001) and lymphopenia at diagnosis (OR, 5.21, p: .006) were risk factors for ICU admission and that HSCT from a mismatched donor (OR, 54.04, p: .028), multisystem inflammatory syndrome in children (MIS-C) (OR, 31.07, p: .003), and LRTD (OR, 10.11, p: .035) were associated with a higher risk for COVID-19-related mortality. CONCLUSION: While COVID-19 is mostly asymptomatic or mild in pediatric transplant recipients, it can cause ICU admission in those with LRTD or lymphopenia at diagnosis and may be more fatal in those who are transplanted from a mismatched donor and those who develop MIS-C or LRTD.

Alantolactone ameliorates graft versus host disease in mice.

The anti-inflammatory and immunosuppressive drugs which are used in the treatment of Graft-versus-Host Disease (GVHD) have limited effects in controlling the severity of the disease. In this study, we aimed to investigate the prophylactic effect of Alantolactone (ALT) in a murine model of experimental GVHD. The study included 4 BALB/c groups as hosts: Naïve (n = 7), Control GVHD (n = 16), ALT-GVHD (n = 16), and Syngeneic transplantation (n = 10). Busulfan (20 mg/kg/day) for 4 days followed by cyclophosphamide (100 mg/kg/day) were administered for conditioning. Allogeneic transplantation was performed with cells collected from mismatched female C57BL/6, and GVHD development was monitored by histological and flow cytometric assays. Additionally, liver biopsies were taken from GVHD patient volunteers between ages 2-18 (n = 4) and non-GVHD patients between ages 2-50 (n = 5) and cultured ex vivo with ALT, and the supernatants were used for ELISA. ALT significantly ameliorated histopathological scores of the GVHD and improved GVHD clinical scores. CD8+ T cells were shown to be reduced after ALT treatment. More importantly, ALT treatment skewed T cells to a more naïve phenotype (CD62L+ CD44-). ALT did not alter Treg cell number or frequency. ALT treatment appears to suppress myeloid cell lineage (CD11c+). Consistent with reduced myeloid lineage, liver and small intestine levels of GM-CSF were reduced in ALT-treated mice. IL-6 gene expression was significantly reduced in the intestinal tissue. Ex vivo ALT-treated liver biopsy samples from GVHD patients showed a trend of decrease in pro-inflammatory cytokines but there was no statistical significance. Collectively, the data indicated that ALT may have immunomodulatory actions in a preclinical murine GVHD model.

A Novel Biallelic LCK Variant Resulting in Profound T-Cell Immune Deficiency and Review of the Literature.

Lymphocyte-specific protein tyrosine kinase (LCK) is an SRC-family kinase critical for initiation and propagation of T-cell antigen receptor (TCR) signaling through phosphorylation of TCR-associated CD3 chains and recruited downstream molecules. Until now, only one case of profound T-cell immune deficiency with complete LCK deficiency [1] caused by a biallelic missense mutation (c.1022T>C, p.L341P) and three cases of incomplete LCK deficiency [2] caused by a biallelic splice site mutation (c.188-2A>G) have been described. Additionally, deregulated LCK expression has been associated with genetically undefined immune deficiencies and hematological malignancies. Here, we describe the second case of complete LCK deficiency in a 6-month-old girl born to consanguineous parents presenting with profound T-cell immune deficiency. Whole exome sequencing (WES) revealed a novel pathogenic biallelic missense mutation in LCK (c.1393T>C, p.C465R), which led to the absence of LCK protein expression and phosphorylation, and a consecutive decrease in proximal TCR signaling. Loss of conventional CD4+ and CD8+ αßT-cells and homeostatic T-cell expansion was accompanied by increased γδT-cell and Treg percentages. Surface CD4 and CD8 co-receptor expression was reduced in the patient T-cells, while the heterozygous mother had impaired CD4 and CD8 surface expression to a lesser extent. We conclude that complete LCK deficiency is characterized by profound T-cell immune deficiency, reduced CD4 and CD8 surface expression, and a characteristic TCR signaling disorder. CD4 and CD8 surface expression may be of value for early detection of mono- and/or biallelic LCK deficiency.

Central nervous system thrombosis in pediatric acute lymphoblastic leukemia in Turkey: A multicenter study.

BACKGROUND: In patients with acute lymphoblastic leukemia (ALL), the risk of thromboembolism increases due to hemostatic changes secondary to the primary disease and due to treatment-related factors. In this multicenter study, we aimed to research the frequency of central nervous system (CNS) thrombosis occurring during treatment, hereditary and acquired risk factors, clinical and laboratory features of patients with thrombosis, treatment approaches, and thrombosis-related mortality and morbidity rates in pediatric ALL patients. PROCEDURE: Pediatric patients who developed CNS thrombosis during ALL treatment from 2010 to 2021 were analyzed retrospectively in 25 different Pediatric Hematology Oncology centers in Türkiye. The demographic characteristics of the patients, symptoms associated with thrombosis, the stage of the leukemia treatment during thrombosis, the anticoagulant therapy applied for thrombosis, and the final status of the patients recorded through electronic medical records were determined. RESULTS: Data from 70 patients with CNS thrombosis during treatment, out of 3968 pediatric patients with ALL, were reviewed. The incidence of CNS thrombosis was 1.8% (venous: 1.5 %; arterial: 0.03%). Among patients with CNS thrombosis, 47 had the event in the first 2 months. Low molecular weight heparin (LMWH) was the most commonly used treatment with a median of 6 months (min-max: 3-28 months). No treatment-related complications occurred. Chronic thrombosis findings occurred in four patients (6%). In five (7%) patients who developed cerebral vein thrombosis, neurological sequelae (epilepsy and neurological deficit) remained. One patient died related to thrombosis, and the mortality rate was 1.4%. CONCLUSION: Cerebral venous thrombosis and, less frequently, cerebral arterial thrombosis may develop in patients with ALL. The incidence of CNS thrombosis is higher during induction therapy than during other courses of treatment. Therefore, patients receiving induction therapy should be monitored carefully for clinical findings suggestive of CNS thrombosis.

Antibody Response against Vaccine Antigens in Children after TCRαß-Depleted Haploidentical Stem Cell Transplantation: Is It Similar to That in Recipients with Fully Matched Donors?

Recipients of hematopoietic stem cell transplantation (HSCT) with HLA-mismatched donors are more immune suppressed than those with fully matched donors. The immunologic response to vaccines also may differ in HLA-mismatched haploidentical HSCT recipients. In this study, we aimed to evaluate the antibody response to vaccines in pediatric TCRαß-depleted haploidentical HSCT recipients. This longitudinal study included a study group of 21 children who underwent haploidentical HSCT without CD19 depletion and with TCRαß depletion and a control group of 38 children who underwent fully matched donor HSCT. Antibody levels were quantified by serologic tests before vaccination and after each dose against tetanus, diphtheria, pneumococcus, hepatitis B, hepatitis A, measles, rubella, mumps, and varicella. The median recipient age was significantly lower (P = .037) and the median donor age was significantly higher (P = .000) in the haploidentical group compared with the fully matched group. At the months 1, 3, 6, 9 and 12 post-transplantation, the median CD4, CD8, and CD19 cell counts and lymphocyte counts were similar in the haploidentical and fully matched groups. The median natural killer cell count was higher in the haploidentical group at the months 1, 3, and 6 post-transplantation (P = .001, .006, and .004, respectively). The median time to first vaccination was similar in the 2 groups (12.5 [range, 11 to 14] months for the haploidentical group and 11 [range, 9 to 13] months for the fully matched group; P = .441). Seroprotection rates were 100% in both groups after the second and third doses of diphtheria vaccine, the third dose of tetanus vaccine, the third dose of hepatitis B vaccine, the second and third doses of pneumococcal conjugate vaccines (PCV13), and pneumococcal polysaccharide vaccine (PSPV23), although lower after the initial doses and before vaccination. Seroprotection for hepatitis A, rubella, and varicella was >90% in the fully matched group and 100% for the haploidentical group after the second doses. Measles and mumps seroprotection rates were >80% in the haploidentical group and approximately 70% for the fully matched group after the second dose. Antibody response and seroprotection rates against vaccine antigens were similar in the haploidentical group and the fully matched when revaccination was started at 12 months post-transplantation. These findings support the idea that TCRαß-depleted haploidentical HSCT recipients can be revaccinated according to the same vaccination schedule as fully matched HSCT recipients. Revaccination earlier after transplantation and vaccine responses for recipients of different types of HSCT should be evaluated in future studies.

Aceruloplasminemia presenting with microcytic anemia in a Turkish boy due to a novel pathogenic variant.

Aceruloplasminemia inherited autosomal recessively in the ceruloplasmin gene is a progressive disease with iron accumulation in various organs such as the brain, liver, pancreas, and retina. Ceruloplasmin gene encodes ceruloplasmin protein, which has ferroxidase activity and is involved in copper and iron metabolism. Progressive neurotoxicity, retinopathy, and diabetes may develop in about 40-60 decades. In addition, microcytic anemia accompanied by high ferritin and low ceruloplasmin level that develop at earlier ages can be first manifestation. Iron chelation may be utilized in the treatment to reduce the toxicity. Early diagnosis and treatment may delay the onset of symptoms. A 14-year-old male patient was followed up with microcytic anemia since an eight-years old. Anemia was accompanied by microcytosis, high ferritin, and low copper and ceruloplasmin levels. A novel homozygous c.690delG variant was detected in ceruloplasmin by whole exome sequencing. Clinical, laboratory and imaging findings of the patient demonstrated aceruloplasminemia. We present a boy with persistent microcytic anemia of the first manifestation at the age of eight, as the youngest case of aceruloplasminemia in the literature. Thereby, aceruloplasminemia should be kept in mind in the etiology of microcytic anemia whose cause couldn't found in childhood.

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.

A teenager boy with a novel variant of Sitosterolemia presented with pancytopenia.

BACKGROUND: Sitosterolemia, also known as phytosterolemia, results from increased intestinal absorption of plant sterols and decreased intestinal and biliary excretion of sterols, resulting in increased levels of plant sterols in the plasma. The most common symptoms include xanthomas, premature atherosclerosis, hemolytic anemia and macrothrombocytopenia, however delayed diagnosis or misdiagnosis also occur. PATIENT AND METHODS: Clinical exome sequencing was performed on a 10-year-old boy whom we followed up with signs of pancytopenia accompanied by macrothrombocytopenia and stomatocytosis. In addition, the blood sterol levels of the patient and his family were studied. RESULTS: A novel homozygous c.904 + 5G > C intronic variant was detected in ABCG5 gene in index case. The mother and father were identified as carriers. The blood plant sterol levels of the patient and his family were studied, and the levels in the patient confirmed Sitosterolemia. Sitosterol levels decreased dramatically with restricted diet and ezetimibe treatment. CONCLUSION: In children, signs of Sitosterolemia may be subtle and the only symptom may be hematological. Therefore, Sitosterolemia should be kept in mind in children with stomatocytosis and macrothrombocytopenia.

Social exclusion and behavior problems in adolescents with cancer and healthy counterparts.

PURPOSE: This cross-sectional study was conducted to determine social exclusion, internalized and externalized behavioral problems in adolescents with cancer and to compare them with healthy counterparts. DESIGN AND METHODS: The sample consisted of adolescents age 10-19 years (N = 70) followed up in the hemato-oncology outpatient clinic of a tertiary hospital and healthy adolescents age 10-19 years (N = 92) who were studying in secondary and high schools. The data were collected with a questionnaire for adolescents with cancer and healthy adolescents, The Ostracism Experience Scale for Adolescents (OES-A), Youth Externalizing Behavior Screener (YEBS), and Youth Internalizing Problems Screener (YIPS). RESULTS: The OES-A mean scores of cancer and healthy adolescents in the study were 35.68 ± 9.38 and 27.64 ± 5.35 (p ≤ 0.001), the YEBS mean scores were 23.51 ± 4.88 and 20.52 ± 5.42 (p ≤ 0.001), and the YIPS mean scores were 21.72 ± 6.48 and 19.18 ± 7.60 (p = 0.007), respectively. There was a low-level positive correlation between the mean scores of the OES-A and YEBS (r = 0.345, p < 0.05) and mean scores of the YEBS and YIPS (r = 0.308, p < 0.05) of adolescents with cancer. CONCLUSIONS: Adolescents with cancer had higher scores on social exclusion, internalized and externalized behavioral problems than healthy counterparts in the current study. PRACTICE IMPLICATIONS: The current study should lead pediatric oncology nurses to be more aware of social exclusion and internalized and externalized behavioral problems in adolescents with cancer after clinical treatment, and to provide appropriate psycho-oncological care.

Common Variable Immunodeficiency, Autoimmune Hemolytic Anemia, and Pancytopenia Associated With a Defect in IKAROS.

OBJECTIVE: Mutations in IKZF1, which encodes Ikaros family zinc finger 1 (IKAROS) transcription factor, are associated with recurrent infections, cytopenia, autoimmune diseases, and hematologic malignancies. Diverse clinical phenotypes resulting from IKZF1 mutations include pulmonary fungal infections, cytopenia, autoimmune hemolytic anemia (AIHA), and malignancies. In this study, we aimed to assess the DNA-binding ability and pericentromeric (PC) localization of a variant of IKZF discovered in a patient. MATERIALS AND METHODS: DNA-binding ability of a pathogenic IKZF variant was tested using electrophoretic mobility shift assay and PC localization of the variant was assessed by immunofluorescent microscopy in NIH3T3 cells. RESULTS: Clinical features of a 3-month-old male infant who underwent hematopoietic stem cell transplantation because of an IKZF1 mutation-associated common variable immunodeficiency, AIHA, and pancytopenia are described. DNA studies revealed a heterozygous missense variant (IKZF1 NM_006060 c.427C>T; p.R143W). Cotransfection studies revealed that mutant R143W has a partial dominant-negative effect over PC targeting and DNA binding. CONCLUSIONS: IKZF1 mutation must be kept in mind if neonatal AIHA, common variable immunodeficiency, and pancytopenia are observed.

Hepatitis-associated aplastic anemia in pediatric patients: single center experience.

INTRODUCTION: Hepatitis-associated aplastic anemia is a rare type of acquired aplastic anemia that occurs after hepatitis. This study investigated cases with hepatitis-associated aplastic anemia. METHODS: The files of patients with hepatitis-associated aplastic anemia who were followed up in our hospital between 2011-2019 were reviewed retrospectively. RESULTS: A total of 15 patients with hepatitis-associated aplastic anemia (10 males, 5 girls; mean age 10.26 ± 3.61 years) were analyzed. The mean duration between hepatitis and aplastic anemia was 5.06 ± 4.19 months. The majority of patients had mild hepatitis. The causes of hepatitis were detected only in six patients: three had hepatitis B, one had hepatitis A, one had autoimmune hepatitis and, one had a hydatid cyst. The cause of hepatitis was not found in nine patients. Only one patient with hepatitis-associated aplastic anemia developed spontaneous remission, and the others required immunosuppressive therapy and/or hematopoietic stem cell transplantation. Only one patient died because of sepsis. The other patients are still under follow-up and treatment. CONCLUSION: Patients with hepatitis-associated aplastic anemia, mostly of unknown cause, can be successfully treated with immunosuppressive therapy and/or hematopoietic stem cell transplantation.

Vena cava superior syndrome in the children with mediastinal tumors: Single-center experience.

OBJECTIVE: Vena cava superior syndrome comprises various symptoms of compression of vena cava superior. The results of increased venous pressure in the upper body may cause edema of the head and neck associated with cyanosis, plethora and distended subcutaneous vessels. Vena cava superior syndrome is rare in childhood. Therefore, we planned this retrospective study. METHODS: The retrospective study was carried out on the children with mediastinal tumors in the Department of Pediatric Hematology-oncology, Erciyes University Faculty of Medicine, Kayseri, Turkey , from January 2010 to December 2017. Diagnostic procedures included hematological investigations, chestradiography, thoracic computed tomography, echocardiography and lymph node or mediastinal biopsy. RESULTS: In this study, 19 (five were female) of 41 patients with mediastinal tumors had Vena cava superior syndrome. Diagnosis included Hodgkin's lymphoma in seven (37%), non-Hodgkin's lymphoma in six (32%), acute T- lymphoblastic leukemia in four (21%), neuroblastoma and anaplastic round cell sarcoma in one each respectively. All of the 19 patients' facial swelling, venous distention and mediastinal widening. All patients received intravenous corticosteroids (0.6 mg/kg dexamethasone). Furthermore, the patient with anaplastic round cell sarcoma received emergency radiotherapy. No patients died because of Vena cava superior syndrome. CONCLUSION: Vena cava superior syndrome is a medical emergency that requiresurgent treatment. Vena cava superior syndrome studies in children are rare. In this retrospective study, we found that the most common cause of Vena cava superior syndrome was Hodgkin's lymphoma different from literature.

Congenital afibrinogenemia in a 4-year-old girl complicated with acute lymphoblastic leukemia.

BACKGROUND: Congenital fibrinogen deficiency is one of the rare inherited coagulation disorders. Congenital fibrinogen deficiency complicated with a hematological malignancy can be life threatening. CASE: We present a four-year-old girl with congenital fibrinogen deficiency complicated with acute lymphoblastic leukemia. CONCLUSION: This case aims to highlight therapeutic approaches for the management of afibrinogenemia patients with acute leukemia.

A Rare Case of Activated Phosphoinositide 3-Kinase Delta Syndrome (APDS) Presenting With Hemophagocytosis Complicated With Hodgkin Lymphoma.

Gain of function mutations in the p110δ catalytic subunit of the phosphatidylinositol-3-OH kinase (PIK3CD) classified as activated phosphoinositide 3-kinase delta syndrome (APDS) are the cause of a primary immunodeficiency characterized by recurrent sinopulmonary infections, and lymphoproliferation. Previously, autoimmunity and Epstein-Barr virus-related B-cell lymphoma have been documented for patients with APDS; here, we present a case that extends the picture, as the patient shows the full diagnostic criteria of hemophagocytic lymphohistiocytosis at 6 months of age. He experienced Hodgkin lymphoma as a 2.5-year-old baby. Next-generation sequencing returned a de novo heterozygous missense variant in PIK3CD (LRG_191t1: c.3061G>A; p.Glu1021Lys), confirming the primary immunodeficiency. After 2 courses of ifosfamide, cisplatin, and etoposide combined with brentuximab, the patient successfully underwent allogeneic hematopoietic stem cell transplantation from his HLA full matched sister, and he has been well for 18 months after that. The hematologist treating Hodgkin lymphoma and/or hemophagocytic lymphohistiocytosis should be vigilant about the possible underlying immune deficiency, and they should consider APDS in their differential diagnosis.

Different Clinical Presentation of 3 Children With Familial Hemophagocytic Lymphohistiocytosis With 2 Novel Mutations.

Although familial hemophagocytic lymphohistiocytosis (FHL) generally manifest with a combination of unremitting fever, hepatosplenomegaly, and pancytopenia; unusual presentations should also be taken into account. Herein, we present 3 FHL cases with 2 novel mutations with different initial presentations. The first patient bearing a homozygous truncation mutation in UNC13D (c.2650C>T.p.Gln884Ter) presented with central nervous system involvement and skin rash. The patient responded to the HLH-2004 protocol, and allogenic hematopoietic stem cell transplantation was performed from her healthy sister. The second and third patients with homozygous splice site mutation (c.430-1G>A) in STXBP2 were siblings who presented at birth with fevers, elevated aspartate aminotransferase, alanine aminotransferase, and hyperferritinemia but did not fulfill FHL criteria. The last 2 infants died despite intervention. Hematologists should be vigilant about the different presentation of FHL in children.

Twenty children with non-Wilms renal tumors from a reference center in Central Anatolia, Turkey

Background/aim: Non-Wilms renal tumors (NWRTs) are rarely encountered in children. The aim of this study is to determine the treatment strategies, prognosis, outcomes, and survival of children with NWRTs at Erciyes University in Kayseri, Turkey. Materials and methods: Medical records of all patients (n = 20) treated for NWRTs over a 23-year period (1995­2018) were reviewed retrospectively. Results: There was male predominance (female/male: 7/13); the median age at diagnosis was 3.2 years old (0.1­13.5 years old). The major histological groups included mesoblastic nephroma (MBN), (n: 5, 25%), malignant rhabdoid tumor (MRT), (n: 5, 25%), renal cell carcinoma, (n: 3, 15%), inflammatory myofibroblastic tumor (n: 2, 10%), multilocular cystic renal tumors (n: 2, 10%), metanephric adenoma (n: 1, 5%), renal neuroblastoma (n: 1, 5%), and bilateral renal Ewing sarcoma/primitive neuroectodermal tumor (ES/PNET) (n: 1, 5%). All of the patients with NWRTs had radical nephrectomy except the child with bilateral renal ES/PNET. Six children died because of progressive disease; the mortality rate was 30% (n: 6). Conclusion: We have made the first report of bilateral renal involvement of ES/PNET in the English medical literature. Physicians dealing with pediatric renal masses should be alert to the high mortality rate in children with MRT, MBN, and ES/PNET and they should design substantial management plans for NWRTs.

CD137 deficiency causes immune dysregulation with predisposition to lymphomagenesis.

Dysregulated immune responses are essential underlying causes of a plethora of pathologies including cancer, autoimmunity, and immunodeficiency. We here investigated 4 patients from unrelated families presenting with immunodeficiency, autoimmunity, and malignancy. We identified 4 distinct homozygous mutations in TNFRSF9 encoding the tumor necrosis factor receptor superfamily member CD137/4-1BB, leading to reduced, or loss of, protein expression. Lymphocytic responses crucial for immune surveillance, including activation, proliferation, and differentiation, were impaired. Genetic reconstitution of CD137 reversed these defects. CD137 deficiency is a novel inborn error of human immunity characterized by lymphocytic defects with early-onset Epstein-Barr virus (EBV)-associated lymphoma. Our findings elucidate a functional role and relevance of CD137 in human immune homeostasis and antitumor responses.