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Krzysztof Czyzewski,1 Magdalena Dziedzic,1 Malgorzata Salamonowicz,2 Jowita Fraczkiewicz,2 Olga Zajac-Spychala,3 Agnieszka Zaucha-Prazmo,4 Jolanta Gozdzik,5 Przemyslaw Galazka,6 Natalia Bartoszewicz,1 Ewa Demidowicz,1 Jan Styczynski1 1Department of Pediatric Hematology and Oncology, Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University in Torun, Bydgoszcz, Poland; 2Department of Pediatric Transplantation, Oncology and Hematology, Medical University, Wroclaw, Poland; 3Department of Pediatric Oncology, Hematology and Transplantology, University of Medical Sciences, Poznan, Poland; 4Department of Pediatric Hematology, Oncology and Stem Cell Transplantation, Medical University, Lublin, Poland; 5Stem Cell Transplant Center, University Children’s Hospital, Department of Clinical Immunology and Transplantology, Jagiellonian University Collegium Medicum, Krakow, Poland; 6Department of General and Oncological Surgery for Children and Adolescents, Collegium Medicum, Nicolaus Copernicus University Torun, Bydgoszcz, PolandCorrespondence: Krzysztof CzyzewskiDepartment of Pediatric Hematology and Oncology, Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University in Torun, Ul. Sklodowskiej-Curie 9, Bydgoszcz 85-094, PolandTel +48 52 585 48 60Fax +48 52-585 4087Email k.czyzewski@cm.umk.plObjective: The analysis of epidemiology, risk factors and outcome of viral infections in children and adolescents after hematopoietic cell transplantation (HCT).Methods: In this multicenter nationwide study a total of 971 HCT procedures (741 allo-HCT; 230 auto-HCT) over a period of 6 years were analyzed.Results: During this period 801 episodes of viral infections were diagnosed in 442 patients. The incidence of viral infections was 57.9% in allo-HCT and 4.8% in auto-HCT patients. The most frequent infections after allo-HCT were caused by cytomegalovirus (CMV), polyoma BK virus (BKV) and Epstein–Barr virus (EBV). The majority of infections occurred within the first 4 months after allo-HCT and over 80% required pharmacotherapy or symptomatic therapy. The median time of treatment of specific viral infection ranged from 7 (for EBV) to 24 (for CMV) days. The highest mortality was observed in case of CMV infection. The risk factors for viral infections were allo-HCT, acute leukemia, acute and chronic graft versus host disease (a/cGVHD), and matched unrelated donor (MUD)/mismatched unrelated donor (MMUD)-HCT. The risk factor for death from viral infection were CMV-IgG seropositivity in acute lymphoblastic leukemia recipient, and MUD/MMUD-HCT. The incidence of EBV infection requiring pre-emptive treatment with rituximab in allo-HCT children was 19.3%. In 30.8% cases of EBV infection, these episodes were preceded by other viral infection and treated with antivirals, which did not prevent development of EBV-DNA-emia with need of rituximab treatment in 81.5% cases. In 47.7% of these cases, GVHD was a factor enabling development of significant EBV-DNA-emia during antiviral therapy of other infection.Conclusion: We have shown that antiviral drugs do not prevent EBV reactivation in allo-HCT pediatric patients.Keywords: children, EBV, HCT, infectious complications, risk factors analysis, viral infections

Krzysztof Czyzewski,1 Przemyslaw Galazka,2 Patrycja Zalas-Wiecek,3 Olga Gryniewicz-Kwiatkowska,4 Agnieszka Gietka,4 Katarzyna Semczuk,5 Liliana Chelmecka-Wiktorczyk,6 Iwona Zak,7 Malgorzata Salamonowicz,8 Jowita Fraczkiewicz,8 Olga Zajac-Spychala,9 Ewa Bien,10 Marcin Plonowski,11 Pawel Wawrykow,12 Filip Pierlejewski,13 Zuzanna Gamrot,14 Zofia Malas,15 Weronika Stolpa,16 Jakub Musial,17 Jan Styczynski11Department of Pediatric Hematology and Oncology, Collegium Medicum, Nicolaus Copernicus University Torun, Bydgoszcz, Poland; 2Department of General and Oncological Surgery for Children and Adolescents, Collegium Medicum, Nicolaus Copernicus University Torun, Bydgoszcz, Poland; 3Department of Microbiology, Collegium Medicum, Nicolaus Copernicus University Torun, Bydgoszcz, Poland; 4Department of Oncology, Children’s Memorial Health Institute, Warsaw, Poland; 5Department of Microbiology, Children’s Memorial Health Institute, Warsaw, Poland; 6Department of Pediatric Oncology and Hematology, University Children’s Hospital, Jagiellonian University, Collegium Medicum, Krakow, Poland; 7Department of Microbiology, University Children’s Hospital, Jagiellonian University, Collegium Medicum, Krakow, Poland; 8Department of Pediatric Stem Cell Transplantation, Hematology and Oncology, Medical University, Wroclaw, Poland; 9Department of Pediatric Oncology, Hematology and Transplantology, University of Medical Sciences, Poznan, Poland; 10Department of Pediatrics, Hematology and Oncology, Medical University, Gdansk, Poland; 11Department of Pediatric Oncology and Hematology, Medical University, Bialystok, Poland; 12Department of Pediatrics and Pediatric Oncology, Pomeranian Medical University, Szczecin, Poland; 13Department of Pediatric Oncology and Hematology, Medical University, Lodz, Poland; 14Division of Pediatric Hematology and Oncology, Chorzow City Hospital, Chorzow, Poland; 15Division of Pediatric Hematology and Oncology, Children Hospital, Olsztyn, Poland; 16Division of Pediatric Oncology, Hematology and Chemotherapy, Department of Pediatric, Silesian Medical University, Katowice, Poland; 17Department of Pediatric Oncohematology, Medical Faculty University of Rzeszow, Clinical Provincial Hospital No. 2, Rzeszow, PolandObjectives: The analysis of epidemiology, risk factors and outcome of infections in children with malignant bone tumors (MBT) undergoing chemotherapy.Methods: In this retrospective nationwide multicenter cross-sectional study, a total number of 126 children with MBT including 70 with Ewing sarcoma (ES) and 56 with osteosarcoma (OSA) were screened for infections over a period of 72 consecutive months.Results: The risk of infection was 7.15-fold higher in patients with ES as compared to the OSA group, especially concerning bacterial infections (4.1-fold increase risk). Bacterial infections occurred in 74.3% patients with ES and in 41.1% with OSA. The median time from diagnosis to first infection was 4.9 months. 33.0% of bacterial episodes were diagnosed as bloodstream (BSI), 31.1% as gastrointestinal tract, 30.1% as urinary tract infection. Infection-related mortality (IRM) from bacterial infection was 6% and 15% in ES and OSA patients, respectively. Cumulative incidence was 7.1% for invasive fungal disease and 6.3% for viral infections. The only significant risk factor for IRM was time to infection ≥5 months since the beginning of chemotherapy. All patients who have died from infection had BSI and were in neutropenia.Conclusions: Infections in the children with MBT in our study occurred with high frequency, especially in patients with ES. The most frequent were bacterial infections, while fungal and viral infections were episodic. Among the bacterial infections, bloodstream, urinary tract and gastrointestinal tract infections occurred with similar frequency. All deceased patients died due to BSI. Bacterial infection occurring ≥5 months since the beginning of chemotherapy was a risk factor for death.Keywords: infectious complications, risk factors analysis, Ewing sarcoma, osteosarcoma, malignant bone tumor, children

Background: Infections caused by Stenotrophomonas maltophilia (SM) have documented high mortality rate in immunocompromised patients., Aim: This nationwide multicenter study was performed to analyze the epidemiology of SM infections in children undergoing anticancer therapy (pediatric hematology and oncology [PHO]) or hematopoietic cell transplantation (HCT) over 2012-2019, including incidence and outcome of SM infections, as well as treatment regimens and multidrug resistance., Methods: Cumulative incidence of SM infections was calculated using the competing risk analysis from the day of diagnosis (PHO setting) or from the day of transplantation (HCT setting). The Kaplan-Meier method was used to determine survival from infection., Results: During the study period of 8 years, a total number of 1356 HCTs and 7337 children newly diagnosed for malignancy were analyzed. Diagnosis of acute leukemia was a predisposing factor for SM infection. The cumulative incidence of SM infections was comparable in HCT patients in comparison to PHO (0.81% vs. 0.76%). High rate of trimethoprim/sulfamethoxazole susceptibility among SM isolates was observed in both groups of patients (80.8%). Although this was the drug of choice, survival rates from SM infections were significantly lower in HCT than in PHO (45% vs. 85%, P = 0.001, log-rank test). We found the transplant procedure and lack of clinical resolution after 18 days of antibiotic therapy to be independent mortality risk factors., Conclusions: The risk of SM infections and the occurrence of resistant bacterial strains in allo-HCT patients were comparable to PHO patients. Irrespective of target antibiotic therapy, the outcome of SM infections was better in the PHO setting., Competing Interests: The authors have no funding or conflicts of interest to disclose., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Despite advances in haematopoietic stem cell transplant (HSCT) techniques, the risk of serious side effects and complications still exists. Neurological complications, both acute and long term, are common following HSCT and contribute to significant morbidity and mortality. The aetiology of neurotoxicity includes infections and a wide variety of non-infectious causes such as drug toxicities, metabolic abnormalities, irradiation, vascular and immunologic events and the leukaemia itself. The majority of the literature on this subject is focussed on adults. The impact of the combination of neurotoxic drugs given before and during HSCT, radiotherapy and neurological complications on the developing and vulnerable paediatric and adolescent brain remains unclear. Moreover, the age-related sensitivity of the nervous system to toxic insults is still being investigated. In this article, we review current evidence regarding neurotoxicity following HSCT for acute lymphoblastic leukaemia in childhood. We focus on acute and long-term impacts. Understanding the aetiology and long-term sequelae of neurological complications in children is particularly important in the current era of immunotherapy for acute lymphoblastic leukaemia (such as chimeric antigen receptor T cells and bi-specific T-cell engager antibodies), which have well-known and common neurological side effects and may represent a future treatment modality for at least a fraction of HSCT-recipients., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The Reviewer GL declared a past collaboration with several of the authors, AL and MI, to the handling editor. The handling editor declared a shared consortium with the authors at time of review., (Copyright © 2021 Gabriel, Hoeben, Uhlving, Zajac-Spychala, Lawitschka, Bresters and Ifversen.)

Haematopoietic stem cell transplant (HSCT) can be a curative treatment for children and adolescents with very-high-risk acute lymphoblastic leukaemia (ALL). Improvements in supportive care and transplant techniques have led to increasing numbers of long-term survivors worldwide. However, conditioning regimens as well as transplant-related complications are associated with severe sequelae, impacting patients' quality of life. It is widely recognised that paediatric HSCT survivors must have timely access to life-long care and surveillance in order to prevent, ameliorate and manage all possible adverse late effects of HSCT. This is fundamentally important because it can both prevent ill health and optimise the quality and experience of survival following HSCT. Furthermore, it reduces the impact of preventable chronic illness on already under-resourced health services. In addition to late effects, survivors of paediatric ALL also have to deal with unique challenges associated with transition to adult services. In this review, we: (1) provide an overview of the potential late effects following HSCT for ALL in childhood and adolescence; (2) focus on the unique challenges of transition from paediatric care to adult services; and (3) provide a framework for long-term surveillance and medical care for survivors of paediatric ALL who have undergone HSCT., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The reviewer GL declared a past collaboration with one of the authors TD-F to the handling Editor., (Copyright © 2021 Diesch-Furlanetto, Gabriel, Zajac-Spychala, Cattoni, Hoeben and Balduzzi.)

Background: Infectious complications (IC) caused by bacterial strains often impede anticancer therapy. The study aimed to retrospectively analyze bacterial IC that could help predict the risk and optimize the empirical treatment for bacterial infections in pediatric cancer patients. Patients and Methods: Over a 72-month period, all-in 5,599 children with cancer: 2,441 patients with hematological malignancy (HM including acute leukemias, Hodgkin and non-Hodgkin lymphomas [NHLs], and Langerhans cell histiocytosis) and 3,158 with solid tumors (STs including central nervous system tumors, neuroblastoma, Wilms' tumor, soft tissue sarcoma, germ cell tumors, Ewing sarcoma, osteosarcoma, hepatoblastoma, and others) were enrolled into the study. Episodes of bacterial infectious complications (EBICs) confirmed by microbiological findings were reported by each hospital and analyzed centrally. Results: At least 1 EBIC was diagnosed in 2,155 (36.8%) children (1,281 [59.4%] with HM and 874 [40.6%] with ST; p  < 0.001). All-in 4,860 EBICs were diagnosed including 62.2% episodes in children with HM and 37.8% in children with ST ( p  < 0.001). Having analyzed the source of infections, blood stream infections predominated, apart from NHL patients in whom the most common type was gut infections. The profile of bacteria strains was different in HM and ST groups ( p  < 0.001). However, in both groups the most common Gram-negative pathogen was Enterobacteriaceae, with the rate being higher in the HM group. Among Gram-negative strains low susceptibility to ceftazidime, whereas among Enterococcus spp. low susceptibility to vancomycin was noticed. The rate of multidrug-resistant (MDR) pathogens was high, especially for Gram negatives (47.7% vs. 23.9%; p  < 0.001). The survival after infections was comparable for HM and ST patients ( p  = 0.215). Conclusions: The risk of bacterial IC in HM patients was higher than in the ST group. The high rate of MDR strains was detected in pediatric cancer patients, especially in those with HM.

Toxoplasmosis is a potentially fatal complication after hematopoietic cell transplantation (HCT). Pre-transplant seropositivity of graft recipient to Toxoplasma gondii (Nicolle et Manceaux, 1908) is an important factor for disease reactivation after HCT. As toxoplasmosis epidemiology varies all over the world, we performed a Polish nationwide retrospective cohort study to determine the seroprevalence of toxoplasmosis in donors and pediatric allogeneic and autologous HCT recipients and the incidence of clinically evident toxoplasmosis in this patient group. Polish adult donors had higher anti-T. gondii seroprevalence than Polish pediatric donors (28% vs 8%; OR = 4.4; p = 0.02) and allo-HCT recipients (28% vs 17%; OR = 1.9; p = 0.01). Clinically apparent disease occurred in 1% of allo-HCT recipients: it was diagnosed by PCR as cerebral and/or ocular toxoplasmosis and successfully treated with antiprotozoal therapy. Regarding current practice, no prospective screening for infection of T. gondii in pediatric HCT centres is being performed, but, vast majority of HCT pediatric patients are receiving anti-T. gondii active prophylaxis. Since pre-HCT T. gondii serology was not assessed in all HCT; recipients, we propose this test should be a standard practice. Standardisation of management with infection of T. gondii in children after HCT is needed.

The objective of this nation-wide study was to evaluate the epidemiology and profile of bacterial (BI), viral (VI), and invasive fungal disease (IFD) in patients treated for non-Hodgkin lymphoma (NHL) and Hodgkin lymphoma (HL) between the years 2013-2015. In the analyzed period of time, within the studied group of 328 children diagnosed and treated for lymphomas, at least one infectious complication (IC) was diagnosed i.e. 39.3% children. In these patients there were 350 episodes of IC, therein 80.6% episodes of BI, 11.1% episodes of VI, and 8.3% episodes of IFD. In both groups, NHL and HL patients, a stable level of bacterial infections, with an increase in resistance rates, and increased levels of viral and fungal infections were observed. Profile of BI does not depend on lymphoma type, with predominance of Gram-negative bacteria and higher prevalence of MDR pathogens. The overall survival of lymphoma patients with IC was comparable for different types of infections.

Post-transplant lymphoproliferative disorder (PTLD) caused by Epstein-Barr virus (EBV) is a severe complication in high-risk allogeneic hematopoietic stem cell transplant (HSCT) recipients. Central nervous system (CNS) involvement of PTLD is a very rare event in patients with HSCT. As no established standard therapy in CNS-EBV-PTLD is available, the aim of this study was analysis of the safety and efficacy of intrathecal rituximab therapy in a group of eight children and adolescents with CNS-EBV-PTLD. Seven patients responded to therapy: all clinical symptoms and EBV-DNA viral load resolved after a median 2 (range: 1-7) doses of rituximab. However, some magnetic resonance imaging (MRI) changes in brain scan persisted in two patients. In all patients, except one, no adverse events of the therapy were observed. In conclusion, intrathecal rituximab administration seems to be an effective and safe method of treatment of CNS-EBV-PTLD in pediatric stem cell recipients. We recommend this treatment modality for further investigation.