Hematopoietic cell transplantation in severe combined immunodeficiency: The SCETIDE 2006-2014 European cohort

Genetic subgroups; Immune reconstitution; Pretransplantation infectionsSubgrupos genéticos; Reconstitución inmune; Infecciones previas al trasplanteSubgrups genètics; Reconstitució immune; Infeccions prèvies al trasplantamentBackground Hematopoietic stem cell transplantation (HSCT) represents a curative treatment for patients with severe combined immunodeficiency (SCID), a group of monogenic immune disorders with an otherwise fatal outcome. Objective We performed a comprehensive multicenter analysis of genotype-specific HSCT outcome, including detailed analysis of immune reconstitution (IR) and the predictive value for clinical outcome. Methods HSCT outcome was studied in 338 patients with genetically confirmed SCID who underwent transplantation in 2006-2014 and who were registered in the SCETIDE registry. In a representative subgroup of 152 patients, data on IR and long-term clinical outcome were analyzed. Results Two-year OS was similar with matched family and unrelated donors and better than mismatched donor HSCT (P 0.5 × 10e3/μL at +1 year were identified as independent predictors of favorable clinical and immunologic outcome. Conclusion Recent advances in HSCT in SCID patients have resulted in improved OS and EFS in all genotypes and donor types. To achieve a favorable long-term outcome, treatment strategies should aim for optimal naive CD4 T lymphocyte regeneration

Multisystem inflammatory syndrome in children in western countries: decreasing incidence as the pandemic progresses? An observational multicenter international cross-sectional study

Multisystemic inflammatory syndrome temporally associated with SARS-CoV-2 infection in children (MIS-C) has been reported worldwide.1–7 The case definition of MIS-C has been estab- lished by different institutions and organizations such as the US Centers for Disease Control and Prevention (CDC) (May 14, 2020),8 the Royal College of Paediatrics and Child Health in the United Kingdom (RCPCH) (May 1, 2020)9,10 and the World Health Organi- zation (WHO) (May 15, 2020).1Postprint (published version

Serum proteomics reveals hemophagocytic lymphohistiocytosis-like phenotype in a subset of patients with multisystem inflammatory syndrome in children

Children with Multisystem Inflammatory Syndrome in Children (MIS-C) can present with thrombocytopenia, which is a key feature of hemophagocytic lymphohistiocytosis (HLH). We hypothesized that thrombocytopenic MIS-C patients have more features of HLH. Clinical characteristics and routine laboratory parameters were collected from 228 MIS-C patients, of whom 85 (37%) were thrombocytopenic. Thrombocytopenic patients had increased ferritin levels; reduced leukocyte subsets; and elevated levels of ASAT and ALAT. Soluble IL-2RA was higher in thrombocytopenic children than in non-thrombocytopenic children. T-cell activation, TNF-alpha and IFN-gamma signaling markers were inversely correlated with thrombocyte levels, consistent with a more pronounced cytokine storm syndrome. Thrombocytopenia was not associated with severity of MIS-C and no pathogenic variants were identified in HLH-related genes. This suggests that thrombocytopenia in MIS-C is not a feature of a more severe disease phenotype, but the consequence of a distinct hyperinflammatory immunopathological process in a subset of children.</p

Severe Pediatric COVID-19 and Multisystem Inflammatory Syndrome in Children From Wild-type to Population Immunity:A Prospective Multicenter Cohort Study With Real-time Reporting

BACKGROUND: SARS-CoV-2 variant evolution and increasing immunity altered the impact of pediatric SARS-CoV-2 infection. Public health decision-making relies on accurate and timely reporting of clinical data. METHODS: This international hospital-based multicenter, prospective cohort study with real-time reporting was active from March 2020 to December 2022. We evaluated longitudinal incident rates and risk factors for disease severity. RESULTS: We included 564 hospitalized children with acute COVID-19 (n = 375) or multisystem inflammatory syndrome in children (n = 189) from the Netherlands, Curaçao and Surinam. In COVID-19, 134/375 patients (36%) needed supplemental oxygen therapy and 35 (9.3%) required intensive care treatment. Age above 12 years and preexisting pulmonary conditions were predictors for severe COVID-19. During omicron, hospitalized children had milder disease. During population immunity, the incidence rate of pediatric COVID-19 infection declined for older children but was stable for children below 1 year. The incidence rate of multisystem inflammatory syndrome in children was highest during the delta wave and has decreased rapidly since omicron emerged. Real-time reporting of our data impacted national pediatric SARS-CoV-2 vaccination- and booster-policies. CONCLUSIONS: Our data supports the notion that similar to adults, prior immunity protects against severe sequelae of SARS-CoV-2 infections in children. Real-time reporting of accurate and high-quality data is feasible and impacts clinical and public health decision-making. The reporting framework of our consortium is readily accessible for future SARS-CoV-2 waves and other emerging infections.</p

Hematopoietic cell transplantation in severe combined immunodeficiency : The SCETIDE 2006-2014 European cohort

Publisher Copyright: © 2021 The AuthorsBackground: Hematopoietic stem cell transplantation (HSCT) represents a curative treatment for patients with severe combined immunodeficiency (SCID), a group of monogenic immune disorders with an otherwise fatal outcome. Objective: We performed a comprehensive multicenter analysis of genotype-specific HSCT outcome, including detailed analysis of immune reconstitution (IR) and the predictive value for clinical outcome. Methods: HSCT outcome was studied in 338 patients with genetically confirmed SCID who underwent transplantation in 2006-2014 and who were registered in the SCETIDE registry. In a representative subgroup of 152 patients, data on IR and long-term clinical outcome were analyzed. Results: Two-year OS was similar with matched family and unrelated donors and better than mismatched donor HSCT (P 0.5 × 10e3/μL at +1 year were identified as independent predictors of favorable clinical and immunologic outcome. Conclusion: Recent advances in HSCT in SCID patients have resulted in improved OS and EFS in all genotypes and donor types. To achieve a favorable long-term outcome, treatment strategies should aim for optimal naive CD4 T lymphocyte regeneration.Peer reviewe

Late Effects in Pediatric Allogeneic Hematopoietic Stem Cell Transplantation for Nonmalignant Diseases: Proxy- and Patient-Reported Outcomes

Survival rates in pediatric hematopoietic stem cell transplantation (HSCT) for nonmalignant diseases have improved due to advances in conditioning regimens, donor selection, and prophylaxis and treatment of infections and graft-versus-host disease. Insight into the long-term patient-reported outcomes (PROs) after pediatric HSCT for nonmalignant disease is lacking but essential for optimal shared decision making, counseling, and quality of care. The purpose of this research was to determine long-term patient-reported outcomes in allogeneic pediatric HSCT for nonmalignant diseases and to compare these results with Dutch reference data. This single-center cohort study evaluated PROs (PedsQL 4.0, PROMIS item banks), self- or proxy-reported, among patients at ≥2 years after pediatric allogeneic HSCT for nonmalignant disease. Mean scores were compared with those of the Dutch general population. Of 171 eligible patients, 119 participated, for a 70% response rate. The median patient age was 15.8 years (range, 2 to 49 years), and the median duration of follow-up was 8.7 years (range, 2 to 34 years). Indications for HSCT included inborn errors of immunity (n = 41), hemoglobinopathies (n = 37), and bone marrow failure (n = 41). Compared with reference data, significantly lower scores were found in adolescents (age 13 to 17 years) on the Total, Physical Health, and School Functioning PedsQL subscales. Significantly more Sleep Disturbance was reported in children (age 8 to 18 years). On the other hand, significantly better scores were seen on PROMIS Fatigue (age 5 to 7 years) and Pain Interference (age 8 to 18 years) and, in adults (age 19 to 30 years), on Depressive Symptoms and Sleep Disturbance. This study showed better or comparable very long-term PROs in patients after pediatric HSCT for nonmalignant diseases compared with the reference population. Children and adolescents seem to be the most affected, indicating the need for supportive care to prevent impaired quality of life and, more importantly, to amplify their long-term well-being

Late Effects in Pediatric Allogeneic Hematopoietic Stem Cell Transplantation for Nonmalignant Diseases: Proxy- and Patient-Reported Outcomes

Survival rates in pediatric hematopoietic stem cell transplantation (HSCT) for nonmalignant diseases have improved due to advances in conditioning regimens, donor selection, and prophylaxis and treatment of infections and graft-versus-host disease. Insight into the long-term patient-reported outcomes (PROs) after pediatric HSCT for nonmalignant disease is lacking but essential for optimal shared decision making, counseling, and quality of care. The purpose of this research was to determine long-term patient-reported outcomes in allogeneic pediatric HSCT for nonmalignant diseases and to compare these results with Dutch reference data. This single-center cohort study evaluated PROs (PedsQL 4.0, PROMIS item banks), self- or proxy-reported, among patients at ?2 years after pediatric allogeneic HSCT for nonmalignant disease. Mean scores were compared with those of the Dutch general population. Of 171 eligible patients, 119 participated, for a 70% response rate. The median patient age was 15.8 years (range, 2 to 49 years), and the median duration of follow-up was 8.7 years (range, 2 to 34 years). Indications for HSCT included inborn errors of immunity (n = 41), hemoglobinopathies (n = 37), and bone marrow failure (n = 41). Compared with reference data, significantly lower scores were found in adolescents (age 13 to 17 years) on the Total, Physical Health, and School Functioning PedsQL subscales. Significantly more Sleep Disturbance was reported in children (age 8 to 18 years). On the other hand, significantly better scores were seen on PROMIS Fatigue (age 5 to 7 years) and Pain Interference (age 8 to 18 years) and, in adults (age 19 to 30 years), on Depressive Symptoms and Sleep Disturbance. This study showed better or comparable very long-term PROs in patients after pediatric HSCT for nonmalignant diseases compared with the reference population. Children and adolescents seem to be the most affected, indicating the need for supportive care to prevent impaired quality of life and, more importantly, to amplify their long-term well-being

Effect of Busulfan and Treosulfan on Gonadal Function after Allogeneic Stem Cell Transplantation in Children and Adolescents with Nonmalignant Diseases Is Not Exposure-Dependent

With an increasing number of young patients surviving into adulthood after hematopoietic stem cell transplantation (HSCT), gonadal dysfunction becomes an important late effect with significant impact on quality of life. In this retrospective study, we evaluated the exposure of busulfan (Bu) and treosulfan (Treo) in relation to gonadal function in pediatric patients who underwent HSCT for a nonmalignant disease between 1997 and 2018. In the Bu group, 56 patients could be evaluated, and gonadal dysfunction was found in 35 (63%). Lower Bu exposure (ie, cumulative area under the curve [AUC] <70 mg*h/L) was not associated with a reduced risk of gonadal dysfunction (odds ratio [OR], .92; 95% confidence interval [CI], .25 to 3.49; P = .90). In the Treo cohort, 32 patients were evaluable and gonadal insufficiency occurred in 9 patients (28%). Lower Treo exposure (AUC <1750 mg*h/L on day 1) was not associated with a reduced risk of gonadal dysfunction (OR, 1.6; 95% CI, .16 to 36.6; P = .71). Our data do not support the premise that reduced-intensity Bu-based conditioning reduces the risk for gonadal toxicity, and it is unlikely that therapeutic drug monitoring-based reduced treosulfan exposure will further limit the risk of gonadal dysfunction

Safety of radiofrequency ablation in patients with locally advanced, unresectable pancreatic cancer : A phase II study

Introduction: Radiofrequency ablation (RFA) has been proposed as a new treatment option for locally advanced, unresectable pancreatic cancer (LAPC). In preparation of a randomized controlled trial (RCT), the aim of this phase II study was to assess the safety of RFA for patients with LAPC. Materials and methods: Patients diagnosed with LAPC confirmed during surgical exploration between November 2012 and April 2014 were eligible for inclusion. RFA probes were placed under ultrasound guidance with a safety margin of at least 10 mm from the duodenum and 15 mm from the portomesenteric vessels. During RFA, the duodenum was continuously perfused with cold saline to reduce risk for thermal damage. Primary outcome was defined as the amount of major complications (Clavien-Dindo grade ≥III). RFA-related complications were predefined as: pancreatic fistula, pancreatitis, thermal damage to the portomesenteric vessels and duodenal perforation. Results: In total, 17 patients underwent RFA. Delayed gastric emptying (DGE) requiring endoscopic feeding tube placement occurred in 4 patients (24%) as only major complication. Five patients (29%) had a major complication other than DGE. One (6%) RFA-related major complications occurred. One patient (6%) died due to complications from a biliary leak following hepaticojejunostomy. After evaluation of the first 5 patients, gastrojejunostomy was no longer performed routinely. Since then severe DGE seemed to occur less (3/5 vs. 3/12 grade C DGE). Conclusion: RFA is a major, but safe procedure for patients with LAPC if performed with strict predefined safety criteria. A RCT is currently investigating the true effectiveness of RFA in patients with LAPC

Safety of radiofrequency ablation in patients with locally advanced, unresectable pancreatic cancer : A phase II study

Introduction: Radiofrequency ablation (RFA) has been proposed as a new treatment option for locally advanced, unresectable pancreatic cancer (LAPC). In preparation of a randomized controlled trial (RCT), the aim of this phase II study was to assess the safety of RFA for patients with LAPC. Materials and methods: Patients diagnosed with LAPC confirmed during surgical exploration between November 2012 and April 2014 were eligible for inclusion. RFA probes were placed under ultrasound guidance with a safety margin of at least 10 mm from the duodenum and 15 mm from the portomesenteric vessels. During RFA, the duodenum was continuously perfused with cold saline to reduce risk for thermal damage. Primary outcome was defined as the amount of major complications (Clavien-Dindo grade ≥III). RFA-related complications were predefined as: pancreatic fistula, pancreatitis, thermal damage to the portomesenteric vessels and duodenal perforation. Results: In total, 17 patients underwent RFA. Delayed gastric emptying (DGE) requiring endoscopic feeding tube placement occurred in 4 patients (24%) as only major complication. Five patients (29%) had a major complication other than DGE. One (6%) RFA-related major complications occurred. One patient (6%) died due to complications from a biliary leak following hepaticojejunostomy. After evaluation of the first 5 patients, gastrojejunostomy was no longer performed routinely. Since then severe DGE seemed to occur less (3/5 vs. 3/12 grade C DGE). Conclusion: RFA is a major, but safe procedure for patients with LAPC if performed with strict predefined safety criteria. A RCT is currently investigating the true effectiveness of RFA in patients with LAPC