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Endothelial injury indices, such as Endothelial Activation and Stress Index (EASIX), modified EASIX (m-EASIX), and simplified EASIX (s-EASIX) scores, have been previously associated with chimeric antigen receptor-T (CAR-T) cell immunotherapy complications. Soluble urokinase-type plasminogen activator receptor (suPAR), growth differentiation factor-15 (GDF-15), and soluble C5b-9 (sC5b-9) have been described as markers of endothelial injury post-hematopoietic stem cell transplantation. In the current study, we examined whether suPAR, GDF-15, and sC5b-9 levels were associated with endothelial injury indices in adult CAR-T cell recipients. The levels of these markers were measured in patients before CAR-T cell infusion and in healthy individuals with immunoenzymatic methods. We studied 45 CAR-T cell recipients and 20 healthy individuals as the control group. SuPAR, GDF-15, and sC5b-9 levels were significantly higher in the patients' group compared to the healthy control group ( p < 0.001, in all comparisons). SuPAR levels at baseline were associated with the m-EASIX scores calculated at the same time point ( p = 0.020), while suPAR and GDF-15 concentrations were correlated with EASIX scores at day 14 post-infusion ( p < 0.001 in both comparisons). Moreover, sC5b-9 levels were correlated with the s-EASIX scores at infusion ( p = 0.008) and the EASIX scores at day 14 ( p = 0.005). In our study, sC5b9, suPAR, and GDF-15 levels were found to reflect endothelial injury in CAR-T cell recipients.

Background/Objectives: Despite novel biological agents, steroid-dependent or -refractory graft-versus-host disease (GvHD) remains a severe complication of allogeneic hematopoietic cell transplantation (allo-HCT). Extracorporeal photopheresis (ECP) is an alternative, non-immunosuppressive treatment for patients with acute (aGvHD) or chronic (cGvHD) GvHD. The aim of this study was to investigate the safety and efficacy of ECP in the treatment of acute and chronic GvHD; Methods: We prospectively studied 112 patients with cGvHD who received one or more previous lines of treatment and 28 patients with steroid-dependent or refractory grade II-IV aGvHD post-alloHSCT. Results: In terms of severe aGvHD, most of the patients (19/28) responded to ECP treatment, while the five-year overall survival (OS) was 34%. After adjustment for several confounder factors, the reduction in immunosuppression ( p = 0.026) and number of ECP sessions ( p < 0.001) were associated with improved OS. Regarding chronic GvHD, only 19 patients failed to respond to ECP treatment; though significantly lower rates of response were presented in patients with visceral involvement ( p = 0.037) and earlier post-transplant GVHD diagnosis ( p = 0.001). Over a follow-up period of 45.2 [interquartile range (IQR): 5.6-345.1] months, the 5-year cumulative incidence (CI) of cGvHD-related mortality was 21.2% and was significantly reduced in patients with ECP response ( p < 0.001), while the 5-year OS was 65.3%. Conclusions: Our results confirm the safety and efficacy of ECP in patients with GvHD and provide sufficient data for further investigation and the best combination drugs needed such that GvHD will not be the major barrier of allo-HCT in the near future.

Multisystem inflammatory syndrome in children (MIS-C) is a rare but severe hyperinflammatory condition that may occur following SARS-CoV-2 infection. This retrospective, descriptive study of children hospitalized with multisystem inflammatory syndrome in children (MIS-C) in 12 tertiary care centers from 3/11/2020 to 12/31/2021. Demographics, clinical and laboratory characteristics, treatment and outcomes are described. Among 145 patients (95 males, median age 8.2 years) included, 123 met the WHO criteria for MIS-C, while 112 (77%) had serological evidence of SARS-CoV-2 infection. Fever was present in 99%, gastrointestinal symptoms in 77%, mucocutaneous involvement in 68% and respiratory symptoms in 28%. Fifty-five patients (38%) developed myocarditis, 29 (20%) pericarditis and 19 (13%) coronary aneurysms. Among the above cases 11/55 (20%), 1/29 (3.4%) and 5/19 (26.3%), respectively, cardiac complications had not fully resolved at discharge. Underlying comorbidities were reported in 18%. Median CRP value was 155 mg/l, ferritin 535 ng/ml, PCT 1.6 ng/ml and WBC 14.2 × 10 9 /mm 3 . Most patients had elevated troponin (41.3%) and/or NT-pro-BNP (49.6%). Intravenous immunoglobulin plus corticosteroids were used in 117/145 (80.6%), monotherapy with IVIG alone in 13/145 (8.9%) and with corticosteroids alone in 2/145 (1.3%). Anti-IL1 treatment was added in 15 patients (10.3%). Thirty-three patients (23%) were admitted to the PICU, 14% developed shock and 1 required ECMO. Mortality rate was 0.68%. The incidence of MIS-C was estimated at 0.69/1000 SARS-CoV-2 infections. Patients who presented with shock had higher levels of NT-pro-BNP compared to those who did not (p < 0.001). Acute kidney injury and/or myocarditis were associated with higher risk of developing shock., Conclusion: MIS-C is a novel, infrequent but serious disease entity. Cardiac manifestations included myocarditis and pericarditis, which resolved in most patients before discharge. Timely initiation of immunomodulatory therapy was shown to be effective. NT-pro-BNP levels may provide a better prediction and monitoring of the disease course. Further research is required to elucidate the pathogenesis, risk factors and optimal management, and long-term outcomes of this clinical entity., What Is Known: • MIS-C is an infrequent but serious disease entity. • Patients with MIS-C present with multi-organ dysfunction, primarily involving the gastrointestinal and cardiovascular systems., What Is New: • NT-pro-BNP levels may provide a better prediction and monitoring of the disease course. • Acute kidney injury and/or myocarditis were associated with higher risk of developing shock., (© 2024. The Author(s).)

Hematopoietic stem cell transplantation-associated thrombotic microangiopathy (HSCT-TMA) and graft-versus-host disease (GvHD) represent life-threatening syndromes after allogeneic hematopoietic stem cell transplantation (allo-HSCT). In both conditions, endothelial dysfunction is a common denominator, and development of relevant biomarkers is of high importance for both diagnosis and prognosis. Despite the fact that soluble urokinase plasminogen activator receptor (suPAR) and growth differentiation factor-15 (GDF-15) have been determined as endothelial injury indices in various clinical settings, their role in HSCT-related complications remains unexplored. In this context, we used immunoenzymatic methods to measure suPAR and GDF-15 levels in HSCT-TMA, acute and/or chronic GVHD, control HSCT recipients, and apparently healthy individuals of similar age and gender. We found considerably greater SuPAR and GDF-15 levels in HSCT-TMA and GVHD patients compared to allo-HSCT and healthy patients. Both GDF-15 and suPAR concentrations were linked to EASIX at day 100 and last follow-up. SuPAR was associated with creatinine and platelets at day 100 and last follow-up, while GDF-15 was associated only with platelets, suggesting that laboratory values do not drive EASIX. SuPAR, but not GDF-15, was related to soluble C5b-9 levels, a sign of increased HSCT-TMA risk. Our study shows for the first time that suPAR and GDF-15 indicate endothelial damage in allo-HSCT recipients. Rigorous validation of these biomarkers in many cohorts may provide utility for their usefulness in identifying and stratifying allo-HSCT recipients with endothelial cell impairment.

The purpose of this study was to investigate knowledge, principles, and practices concerning the management of children with febrile seizures among pediatricians in Greece. A cross-sectional study was performed across Greece. Pediatricians completed an anonymous and voluntary 11-item questionnaire about their knowledge, attitudes, and practices with respect to the management of febrile seizures; the survey also collected demographic data. It was first administered in paper form in October 2017. This was followed by an online survey performed between June and August of 2018 and publicized by medical boards across Greece. Descriptive statistics and comparisons between groups were conducted with the significance level set at p ≤ 0.05. We recorded 457 responses. Pediatricians admitted to modifying their advice to the parents of children with febrile seizures by suggesting more "aggressive" fever management at low temperatures or systematically (63%), referral to a specialist after any episode of febrile seizures (63%), or hospitalization in a subsequent episode (67%), even though 72% admitted these practices were of no efficacy. Almost one in three pediatricians (28%) believed aggressive management of fever could delay the onset of febrile seizures; increasing age was associated with this perception. A minority (28%) would make parents aware of febrile seizures before a first episode regardless of family history; 38% would do so in the event of family history., Conclusions: Several pediatricians in Greece use outdated and ineffective practices for the management of febrile seizures, despite the availability of updated evidence-based guidelines. Further training of practitioners is needed to bridge this gap., What Is Known: •Aggressive management of fever at low temperatures with antipyretics, referral to a neurologist, and hospitalization are not supported by evidence or recent guidelines on childhood febrile seizures. •Febrile seizures are especially disturbing to uninformed parents, who may be inclined to pursue aggressive but ineffective treatments as a result., What Is New: •Pediatricians in Greece use non-evidence-based practices for the management of febrile seizures, even when they are aware that these practices are not effective. •Older age increases the likelihood that a pediatrician will pursue guideline non-compliant practices in Greece. At the same time, physicians with over 20 years of experience are more likely to inform parents in advance about febrile seizures., (© 2023. The Author(s).)

Objectives: Mass vaccination is the most effective strategy for controlling the COVID-19 pandemic. This study aimed to evaluate the 6-month immunogenicity after BNT162b2-COVID-19 vaccination in adolescents with JIA on TNFi treatment., Methods: This single-centre study included adolescents with JIA treated with TNFi for at least 18 months. Patients received two doses of COVID-19 vaccine (Pfizer-BioNTech) from 15 April to 15 May 2021. Quantitative measurement of IgG antibodies to SARS-CoV-2-spike-protein-1 was performed at 1, 3 and 6 months post-vaccination., Results: Overall, 21 adolescents with JIA in clinical remission at the time of vaccinations were enrolled. None of them discontinued TNFi/MTX treatment at the time of vaccine administration or during the follow-up period. All patients developed a sustained humoral response against SARS-CoV-2 at 1 and 3 months after vaccination (P < 0.05). The antibody levels decreased significantly at 6 months post-vaccination (P < 0.01). The type of JIA did not reveal any differences in the humoral response at 3 (P = 0.894) or 6 months post-vaccination (P = 0.72). No difference was detected upon comparison of the immunogenicity between the different treatment arms (adalimumab vs etanercept) at 3 (P = 0.387) and 6 months (P = 0.526), or TNFi monotherapy vs combined therapy (TNFi plus methotrexate) at 3 (P = 0.623) and 6 months (P = 0.885)., Conclusions: Although mRNA vaccines develop satisfactory immunogenicity at 1 month and 3 months post-vaccination in adolescents with JIA on TNFi, SARS-CoV-2 antibody titres decrease significantly overtime, remaining at lower levels at 6 months. Further collaborative studies are required to determine long-term immunogenicity, real duration of immune protection and the need for a booster vaccine dose., (© The Author(s) 2022. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

In this nationwide retrospective study, a substantial decline in the incidence of multisystem inflammatory syndrome in children over 3 successive pandemic waves characterized by different severe acute respiratory syndrome coronavirus 2 variants was documented-from 3.4 of 1000 to 1.1 of 1000 and finally to 0.25 of 1000 confirmed severe acute respiratory syndrome coronavirus 2 positive cases (P < 0.0001), respectively, whereas clinical findings and severity did not significantly vary., Competing Interests: The authors have no funding or conflicts of interest to disclose., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

A unified surveillance mechanism for hand hygiene and hospital-acquired infections for pediatric wards is lacking in Europe. We managed to setup such a mechanism in 9 pediatric intensive care units in 7 European countries, using World Health Organization's definitions and common methodology which allows for benchmarking among units and countries. Median hand hygiene compliance was found high 82.3% (interquartile range 71.6-94.5%), but gaps in practices were identified., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

This study aims to describe the clinical characteristics and outcome of 92 infants (aged <12 months) with community-acquired coronavirus disease 2019 (COVID-19) between March, 2020 and June, 2021 at a single center in Athens. Infants with COVID-19 developed mild disease (89, 96.7%), and were infected mostly by their household contacts (74, 80.4%). Disease complications were rare, indicating that hospitalization is the result of low threshold for admission rather than disease severity.

Aim: This study aims to construct and validate a new score for diagnosis of complicated appendicitis in children, complicated appendicitis pediatric score (CoAPS), to guide residents' clinical decision-making on choosing the correct patients for immediate surgery, reducing the emergency negative surgeries., Methods: This prospective observational study enrolled two cohorts of patients 5-15 years old. Four hundred and seven consecutive patients were enrolled for the derivation cohort. Demographic data, clinical features, and histopathology data were collected. The outcome measure was the histological diagnosis of gangrenous appendicitis with or without perforation. The score was next validated in a separate cohort of 312 consecutive patients who were classified according to their risk of complicated appendicitis. The diagnostic performance of the score and the potential for the risk stratification to select patients for diagnostic imaging, emergency operative management, and reduce emergency negative operation rates were quantified., Results: A positive "jumping up" test, vomiting, white blood cell >13.5 × 10^3/ml, lymphocytes <18%, and C-reactive protein >50 mg/dl were independent predictors for complicated appendicitis. The final prediction model exhibited an area under the curve of 0.890 (95% confidence interval: 0.859-0.922). The low-risk group demonstrated high sensitivity (90.4%) for complicated appendicitis, while scores 6 or more were very specific (95%) for the disorder. Describing the potential utility of the score, emergency ultrasound imaging would have been postponed in 14.5% of patients ( P = 0.0016), and emergency negative explorations would have been cut by 87%., Conclusion: The CoAPS score could guide residents in emergency management of children with complicated appendicitis reducing hospitalizations and urgent surgeries., Competing Interests: There are no conflicts of interest., (Copyright: © 2022 Journal of Indian Association of Pediatric Surgeons.)

Objective: We surveyed antimicrobials used in Greek pediatric hematology-oncology (PHO) and bone marrow transplant (BMT) units before and after an intervention involving education regarding the 2017 clinical practice guidelines (CPG) for the management of febrile neutropenia in children with cancer and hematopoietic stem-cell transplant recipients., Design: Antibiotic prescribing practices were prospectively recorded between June 2016 and November 2017., Intervention: In December 2017, baseline data feedback was provided, and CPG education was provided. Prescribing practices were followed for one more year. For antibiotic stewardship, days of therapy, and length of therapy were calculated., Setting: Five of the 6 PHO units in Greece and the single pediatric BMT unit participated., Participants: Admitted children in each unit who received the first 15 new antibiotic courses each month., Results: Administration of ≥4 antibiotics simultaneously and administration of antibiotics with overlapping activity for ≥2 days were significantly more common in PHO units in general hospitals compared to children's hospitals. Use of at least 1 antifungal was recorded in ∼47% of the patients before and after the intervention. De-escalation and/or discontinuation of antibiotics on day 6 of initial treatment increased significantly from 43% to 53.5% (P = .032). Although the number of patients requiring intensive care support for sepsis did not change, a significant drop was noted in all-cause mortality (P = .008)., Conclusions: We recorded the antibiotic prescribing practices in Greek PHO and BMT units, we achieved improved prescribing with a simple intervention, and we identified areas in need of improvement., (© The Author(s) 2022.)

To assess the potential benefit from the implementation of the Kaiser Permanente early-onset sepsis calculator (EOS-C), in terms of antibiotic use and requested laboratory tests, in a network of neonatal intensive care units (NICUs) in Greece, and to determine the incidence of early-onset sepsis (EOS) in Greek NICUs, a prospective surveillance study was conducted in 7 NICUs between April 2018 and June 2019. Data were collected for all newborns ≥ 34 weeks' gestation receiving empiric antibiotic therapy within the first 3 days of life. The number of live births and positive blood or cerebrospinal fluid cultures within the first 3 days of life were used for calculation of EOS incidence. Evaluation of possible impact of implementing the calculator was done by comparing the clinicians' recorded management to the calculator's suggested course of action. The unit-specific incidence of culture-proven EOS ranged between 0 and 2.99/1000 live births. The weighted incidence rate for all 7 units was 1.8/1000 live births. Management of EOS guided by the calculator could lead to a reduction of empiric antibiotic initiation up to 100% for the group of "well-appearing" neonates and 86% for "equivocal," lowering exposure to antibiotics by 4.2 and 3.8 days per neonate, respectively. Laboratory tests for blood cultures drawn could be reduced by up to 100% and 68%, respectively. Sensitivity of the EOS-C in identifying neonates with positive blood cultures was high.Conclusion: Management strategies based on the Kaiser Permanente neonatal sepsis calculator may significantly reduce antibiotic exposure, invasive diagnostic procedures, and hospitalizations in late preterm and term neonates. What is Known: • Neonates are frequently exposed to antibiotics for presumed EOS. • The Kaiser Permanente sepsis calculator can reduce antibiotic exposure in neonates.. What is New: • EOS calculator can be an effective antibiotic stewardship tool in a high prescribing country and can reduce invasive diagnostic procedures and mother-baby separation. • Incidence of EOS in Greece is higher compared to other European countries., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: Identifying potential predictive factors for the type of bacteremia (Gram-negative vs. Gram-positive) in children with cancer would be crucial for the timely selection of the appropriate empiric antibiotic treatment., Materials and Methods: Demographic, clinical, and laboratory characteristics of children with cancer and a bacterial bloodstream infection (BSI) (February 1, 2011 to February 28, 2018) in a tertiary pediatric oncology department were retrospectively examined and were correlated with the type of isolated bacteria., Results: Among 224 monomicrobial bacterial BSI episodes, Gram-negative and Gram-positive bacteria were isolated in 110 and 114 episodes, respectively. Gram-negative bacteria were isolated significantly more frequently in girls (Gram-negative/Gram-positive ratio 1.7:1) versus boys (Gram-negative/Gram-positive ratio 0.72:1), P=0.002, in patients with previous BSI episodes (1.4:1) versus those without (0.8:1), P=0.042, and in children with hematologic malignancy (1.3:1) versus those who suffered from solid tumors (0.52:1), P=0.003. Gram-negative BSI episodes were more frequently correlated with a lower count of leukocytes, P=0.009, neutrophils, P=0.009 and platelets, P=0.002, but with significantly higher C-reactive protein (CRP) levels, P=0.049. Female sex, hematologic malignancy, and higher CRP levels remained independent risk factors for Gram-negative BSI in the multivariate analysis. Among neutropenic patients, boys with solid tumors and a recent central venous catheter placement appear to be at increased risk for Gram-positive BSI in the multivariate analysis., Conclusions: Although Gram-negative and Gram-positive BSIs are close to balance in children with cancer, Gram-negative bacteria are more likely to be isolated in girls, children with hematologic malignancies and those with higher CRP level at admission. In contrast, neutropenic boys with solid tumors and a recently placed central venous catheter may be at increased risk for Gram-positive BSI indicating probably the need for initially adding antibiotics targeting Gram-positive bacteria., Competing Interests: The authors declare no conflict of interest., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)