Reduced-Intensity/Reduced-Toxicity Conditioning Approaches Are Tolerated in XIAP Deficiency but Patients Fare Poorly with Acute GVHD.

X-linked inhibitor of apoptosis (XIAP) deficiency is an inherited primary immunodeficiency characterized by chronic inflammasome overactivity and associated with hemophagocytic lymphohistiocytosis (HLH) and inflammatory bowel disease (IBD). Allogeneic hematopoietic cell transplantation (HCT) with fully myeloablative conditioning may be curative but has been associated with poor outcomes. Reports of reduced-intensity conditioning (RIC) and reduced-toxicity conditioning (RTC) regimens suggest these approaches are well tolerated, but outcomes are not well established. Retrospective data were collected from an international cohort of 40 patients with XIAP deficiency who underwent HCT with RIC or RTC. Thirty-three (83%) patients had a history of HLH, and thirteen (33%) patients had IBD. Median age at HCT was 6.5 years. Grafts were from HLA-matched (n = 30, 75%) and HLA-mismatched (n = 10, 25%) donors. There were no cases of primary graft failure. Two (5%) patients experienced secondary graft failure, and three (8%) patients ultimately received a second HCT. Nine (23%) patients developed grade II-IV acute GVHD, and 3 (8%) developed extensive chronic GVHD. The estimated 2-year overall and event-free survival rates were 74% (CI 55-86%) and 64% (CI 46-77%), respectively. Recipient and donor HLA mismatch and grade II-IV acute GVHD were negatively associated with survival on multivariate analysis with hazard ratios of 5.8 (CI 1.5-23.3, p = 0.01) and 8.2 (CI 2.1-32.7, p < 0.01), respectively. These data suggest that XIAP patients tolerate RIC and RTC with survival rates similar to HCT of other genetic HLH disorders. Every effort should be made to prevent acute GVHD in XIAP-deficient patients who undergo allogeneic HCT.

Varicella-zoster virus infection in the pediatric population with acute lymphoblastic leukemia in Poland.

Varicella-zoster virus (VZV) infection in pediatric hemato-oncology patients can be a therapeutic problem when children are exposed to immunosuppression. The aim of this study is to evaluate the incidence of VZV infection, antiviral therapy and outcome in children with ALL treated in polish hemato-oncological centers between 2012 and 2019 years. This study included medical records of 1874 patients, aged 1 to 18 years, with newly diagnosed acute lymphoblastic leukemia. During chemotherapy, 406 children out of 1874 (21.6%) experienced viral infections. The incidence of VZV infection in the whole group children with ALL was 1.8%. Among them, 34 (8.4%) patients were diagnosed with VZV infection. Thirty-five episodes of viral infections were identified. The median time of VCV therapy was 12 days. Herpes zoster infection occurred in 24 (70.6%) children, and varicella in 10 (29.4%) ones. The average time from the start of chemotherapy to the appearance of herpes zoster was 7.26 ± 4.05 months. VZV infection occurred mainly during the maintenance therapy, the reinduction and induction phases. There was no correlation between steroid dosage or type and subsequent zoster. The total lymphocyte count of these patients on the first day of zoster was reduced. No serious complications were observed due to this infection. All patients survived. In conclusion, a low incidence of VZV infection was observed among pediatric patients with ALL in Poland. This analysis indicates that currently used therapeutic methods are effective in children with cancer and VZV infection. The main focus should be on the prevention of delayed chemotherapy.

Infectious complications after hematopoietic stem cell transplantation for primary immunodeficiency in children: A multicenter nationwide study.

PURPOSE: The aim of this nationwide study was to evaluate the characteristics of bacterial infections (BI), invasive fungal disease (IFD), and viral infections (VI) in pediatric patients with PID after allogeneic hematopoietic stem cell transplantation (allo-HSCT). PATIENTS AND METHODS: In total, 114 HSCT recipients were enrolled into the study. At least one infectious complication (IC) was diagnosed in 60 (52.6%) patients aged 0.1-17.7 years, that is, 59.5% with SCID and 49.4% with non-SCID. RESULTS: Among 60 HSCT recipients diagnosed with at least one IC, 188 episodes of infectious complications (EIC) were recorded, that is, 46.8% of BI, 41.5% of VI, and 11.7% of proven/probable IFD. According to PID and HSCT donor type, the incidence of EIC was comparable (P = .679). The localization of infections differed significantly due to PID type (P = .002). After each HSCT donor type, the most common site of infection was GI. Overall, BI caused by Gram-positive strains (59.1%) were prevalent, especially Staphylococcaceae. The multidrug-resistant (MDR) pathogens were diagnosed in 52.3%, especially ESBL + Enterobacteriaceae. The profile of VI was comparable for SCID and non-SCID patients (P = .839). The incidence of IFD was comparable for each PID and HSCT donor type. Survival after infection was 91.5% and was comparable for PID and HSCT donor type. CONCLUSIONS: The rate of patients diagnosed with IC among pediatric PID-HSCT recipients did not depend on PID type, but rather on HSCT donor type. The localization of IC depended on PID and HSCT donor type. Within bacterial infections, predominated Gram-positive strains and the MDR pathogens were responsible for more than half of EIC.

Feasibility and Safety of Treosulfan, Melphalan, and Thiotepa-Based Megachemotherapy with Autologous or Allogeneic Stem Cell Transplantation in Heavily Pretreated Children with Relapsed or Refractory Neuroblastoma.

The prognosis of resistant or relapsing children with neuroblastoma remains very poor, and the search for new therapies is ongoing. In this analysis, we assessed the toxicity of a treosulfan, melphalan, and thiotepa (TMT) regimen in 17 children with recurrent or refractory neuroblastoma who underwent stem cell transplantation (SCT). For allogeneic SCT, fludarabine and antithymocyte globulin were added. The stem cell source was autologous in 8 patients, haploidentical in 8 patients, and a matched unrelated donor in 1 patient. The reported nonhematologic toxicities included grade 3 mucositis, grade 1 to 3 hypertransaminasemia, and in 3 patients, veno-occlusive disease. No neurologic, cardiac, or dermatologic toxicities were observed. The probability of overall survival (OS) in patients with primary resistance was superior to that in patients with relapsed disease (100% versus 22.6%; P = .046). Post-transplantation dinutuximab beta immunotherapy was associated with superior 5-year OS (66.7% versus 11.4%; P = .0007). The use of an allogeneic donor, previous autologous SCT with busulfan and melphalan, and pretreatment with high-dose metaiodobenzylguanidine therapy demonstrated no effect on outcomes. In 4 patients, TMT megatherapy alone was enough to achieve complete remission. The TMT conditioning regimen was well tolerated in heavily pretreated patients with neuroblastoma. The manageable toxicity and addition of new anticancer drugs with optional post-SCT immunotherapy or chemotherapy support further trials with the TMT regimen in patients with neuroblastoma.

Age-dependent determinants of infectious complications profile in children and adults after hematopoietic cell transplantation: lesson from the nationwide study.

Incidence and outcome of microbiologically documented bacterial/viral infections and invasive fungal disease (IFD) in children and adults after hematopoietic cell transplantation (HCT) were compared in 650 children and 3200 adults in multicenter cross-sectional nationwide study. Infections were diagnosed in 60.8% children and 35.0% adults, including respectively 69.1% and 63.5% allo-HCT, and 33.1% and 20.8% auto-HCT patients. The incidence of bacterial infections was higher in children (36.0% vs 27.6%; p < 0.0001). Infections with Gram-negative bacteria were more frequent than Gram-positives in adults (64.6% vs 44.8%; p < 0.0001). Outcome of bacterial infections was better in children (95.5% vs 91.4%; p = 0.0011). The IFD incidence (25.3% vs 6.3%; p < 0.0001) and outcome (88.0% vs 74.9%; p < 0.0001) were higher in children. The incidence of viral infections was higher in children after allo-HCT (56.3% vs 29.3%; p < 0.0001), and auto-HCT (6.6% vs 0.8%; p < 0.0001). Outcome of viral infections was better in children (98.6% vs 92.3%; p = 0.0096). Infection-related mortality was 7.8% in children and 18.4% in adults (p < 0.0001). No child after auto-HCT died of infection. Adult age, mismatched transplants, acute leukemia, chronic GVHD, CMV reactivation, infection with Gram-negatives, and duration of infection > 21 days were risk factors for death from infection. In conclusion, pediatric patients have 2.9-fold higher incidence and 2.5-fold better outcome of infections than adults after HCT.

Infection profile in children and adolescents with bone marrow failures treated with allogeneic hematopoietic stem cell transplantation.

BACKGROUND: The objective of the study was to analyze the profile of infections in children with BMF following alloHCT. METHODS: Data of 169 consecutive children with inherited and acquired BMF treated with alloHCT between 2012 and 2017 in Polish pediatric transplant departments were analyzed in registry-based retrospective study, with respect to the type of infection, and clinical outcome. RESULTS: At least 1 infection was diagnosed in 107/169 patients (60.4%). In total, 182 infections were diagnosed. The most common were VI (96; 52.7%), followed by BI (71; 39.0%), and FI (15; 8.2%), P < .001. The most common etiological factors of VI were as follows: CMV (38.5%), EBV (22.9%), and BK virus (24%); while of BI were as follows: Staphylococcus spp. (17; 23.9%), Enterococcus faecium (10; 14.1%), and Klebsiella pneumoniae (9; 12.7%). No difference was found between the occurrence of infections with respect to donor type, graft source, and conditioning type. GvHD had no impact on the incidence of VI, BI, and FI. Fifteen FI were diagnosed in 12 patients, of which 14 FI were diagnosed in children transplanted for FA. Of total 107 children, 9 died (8.4%), of which 4 (3.7%) due to infections: bacterial sepsis (2) and invasive FI (2). CONCLUSION: Infections in children with BMF following alloHCT remain an important cause of morbidity. Children with FA had high incidence of FI. In our analysis, aGvHD had no impact on the occurrence on infections, although the study was not strong enough to prove such a difference.

Infectious profile in children with ALL during chemotherapy: A report of study group for infections.

INTRODUCTION: The treatment-related mortality in currently published studies of acute lymphoblastic leukemia (ALL) in children is 2-4%, mainly due to infections. The aim of the study was to analyse the incidence, epidemiology, profile of infection and the death rate in children with ALL. PATIENTS AND METHODS: The retrospective analysis included 1363 patients, aged 1-18 years, with newly diagnosed ALL, who were treated in 17 pediatric hematology centers between 2012 and 2017 in Poland. The patients received therapy according to the ALL IC-BFM 2002 and 2009 (International Berlin-Frankfurt-Munster Study Group) protocols. RESULTS: In our study, 726 out of 1363 (53.2%) children were reported to have a microbiologically documented bacterial infection during chemotherapy. 1511 episodes of these infection were diagnosed. A total number of 251/1363 (18.4%) children experienced a viral infection. 304 episodes were documented by PCR test (polymerase chain reaction). A fungal infection was reported in 278 (20.4%) children, including 10.1% of probable, 6.0% of proven, 83% of possible diagnosis. A higher frequency of fungal infection was noted in the recent years. In our material, the rate of death was 2.4%, mainly due to fungal infection. CONCLUSIONS: Our results present the epidemiology of infectious disease in the Polish ALL patient population. The most frequent were bacterial infections, followed by fungal and viral ones. Similar to the previously published data, the mortality rate in our material was 2.4%.

Epidemiology and outcome of invasive fungal disease in children after hematopoietic cell transplantation or treated for malignancy: Impact of national programme of antifungal prophylaxis.

The objective of the study was the analysis of incidence and outcome of invasive fungal disease (IFD) in children treated for malignancy (PHO, paediatric hematology-oncology) or undergoing hematopoietic cell transplantation (HCT) over a period of six consecutive years in nationwide study. A total number of 5628 patients with newly diagnosed malignancies and 971 patients after HCT (741 allo-HCT and 230 auto-HCT) were screened for infectious complications in biennial reports. IFD incidence was lower among PHO patients: 8.8% vs 21.2% (P < .0001) and survival from IFD was better: 94.2% vs 84.1% (P < .0001). Auto-HCT patients had lower incidence (10.9% vs 24.4%) and lower mortality than allo-HCT patients. Introduction of national antifungal prophylaxis programme in HCT and acute leukaemia patients decreased incidence of IFD in HCT (from 23.1% to 13.4%) and AML on conventional chemotherapy (from 36% to 23%) but not in ALL patients during chemotherapy. In multivariate analysis, the incidence of IFD was higher in patients after HCT, diagnosed for ALL, AML or NHL, and in patients > 10 years old. Factors contributing to death with infection were as follows: undergoing HCT, diagnosis of acute leukaemia (ALL or AML) and duration of treatment of infection > 21 days. In conclusion, the incidence of IFD in allo-HCT and in AML patients on chemotherapy has decreased after introduction of national programme of antifungal prophylaxis, while the incidence of IFD in ALL patients on chemotherapy did not change significantly. The outcome of IFD both in PHO and HCT patients has largely improved in comparison with historical international data.

Allogeneic Stem Cell Transplantation after Fanconi Anemia Conditioning in Children with Ataxia-Telangiectasia Results in Stable T Cell Engraftment and Lack of Infections despite Mixed Chimerism.

Ataxia-telangiectasia (A-T) syndrome is an autosomal recessive chromosomal breakage syndrome caused by mutation of the ataxia-telangiectasia mutated gene manifested by progressive neurodegeneration, telangiectasias of sclera and skin, immune deficiency with sinopulmonary infections, and increased incidence of lymphoid malignancies and solid tumors. Three children with A-T underwent allogeneic stem cell transplantation (SCT) using protocols for Fanconi anemia. All 3 patients were engrafted with a mixed donor-recipient chimerism, but the full donor engraftment was observed in the T lymphocyte compartment. Immunologic recovery resulted in T cell production and lack of symptomatic infections. Regular intravenous immunoglobulin supplementation was needed until IgG production recovered, which depended on pretransplant serotherapy. During the observation period patients did not require hospital admission, and none of the transplanted patients developed sinopulmonary infections. Neurologic functions in reported patients were impaired and slowly deteriorated after transplantation, but no immediate toxicities were observed. The following hallmark features of A-T were present after SCT: neurologic symptoms, growth failure, telangiectasia formation, or increased serum alpha fetoprotein. SCT can help control immune deficiency constituting 1 of the features of A-T, and elimination of autologous hematopoiesis reduces the risk of lymphoid malignancies. Resolving crucial problems with qualification for SCT depends on balancing the risk and benefits of transplant therapy.

Incidence, course, and outcome of Clostridium difficile infection in children with hematological malignancies or undergoing hematopoietic stem cell transplantation.

Clostridium difficile infection (CDI) is one of the most common causes of nosocomial infectious diarrhea in children during anticancer therapy or undergoing hematopoietic stem cell transplantation (HSCT) in Europe. Immunosuppression in these patients is a risk factor for CDI. Malignant diseases, age, acute graft-versus-host disease (aGVHD), HLA mismatch, or use of total body irradiation may play an important role in CDI course. The aim of this study was to evaluate the incidence, course, and outcome of CDI in children treated for malignancy or undergoing HSCT. Between 2012 and 2015, a total number of 1846 patients were treated for malignancy in Polish pediatric oncological centers (PHO group) and 342 underwent transplantation (HSCT group). In PHO group, episodes of CDI occurred in 210 patients (14%). The incidence of CDI was higher in patients with hematological malignancies in comparison to that with solid tumors. Patients with acute myeloblastic leukemia had shorter time to episode of CDI than those with acute lymphoblastic leukemia. Patients over 5 years and treated for acute leukemia had more severe clinical course of disease in PHO group. In HSCT group, CDI occurred in 29 (8%) patients. The incidence of CDI was higher in patients transplanted for acute leukemia. The recurrence rate was 14.7% in PHO and 20.7% in HSCT patients. CDI incidence was highest in patients with hematological malignancies. Most of patients experienced mild CDI. Age < 5 years and diagnosis other than acute leukemia were the positive prognostic factors influencing clinical CDI course.

Influence of Iron Overload on Immunosuppressive Therapy in Children with Severe Aplastic Anemia.

Children with severe aplastic anemia (AA) require multiple transfusions of the red blood cells during the immunosuppressive therapy. This leads to iron overload and manifests as elevated levels of ferritin in blood. The aim of this study was a retrospective analysis of the influence of the elevated serum ferritin on the overall survival, event-free survival, the risk of relapse, and response to treatment in children with AA during immunosuppressive therapy. We analyzed 38 children with AA (19 girls, 19 boys, aged 2-17 years) treated according to the obligatory protocol for AA in Poland. The response rate was assessed on days 84, 112, and 360. Patients were divided into three groups: group I consisted of children with ferritin below 285 ng/mL (6 children), group II with ferritin between 286 and 1,000 ng/mL (13 children), and group III ferritin>1,000 ng/mL (19 children). Kaplan-Meier plot was used to estimate the overall survival and event-free survival. We found the overall survival did not differ between the three groups. Event-free survival was significantly shorter (p=0.03) in patients with ferritin levels>1,000 ng/mL compared with the groups with ferritin bellow 1,000 ng/mL. The time to relapse was significantly shorter in group III than in the other two groups (p=0.02). We also found the differences in the treatment response at day 84 (p=0.03) and day 112 (p<0.0001) of immunosuppressive therapy. These findings confirm a negative influence of iron overload in children with AA on the effect of treatment and the risk of relapse.

Respiratory and systemic infections in children with severe aplastic anemia on immunosuppressive therapy.

In the present study we investigated the occurrence of systemic and respiratory infections in a cohort of 123 children with severe acquired aplastic anemia (SAA) on immunosuppressive therapy (IST). We recorded 101 episodes of infection in 77 patients (62.6 %). Pneumonia was among the most frequently observed clinical forms of infection (17 cases - 16.8 %). In the entire group, 23 children died, mostly in the course of fatal sepsis (15/23) and in 3 cases because of pneumonia complications. All patients were treated with horse (h-ATG) or rabbit antithymocyte globulin (r-ATG) supplemented with cyclosporine and corticosteroids. The crude incidence rate for serious infections in h-ATG group and r-ATG group was comparable. The relative risk of infectious complications was lower in patients treated with granulocyte colony stimulating factors (G-CSF) by 36 % (RR 0.64; p < 0.0001). The analysis confirmed that respiratory tract and disseminated infections comprise a very serious clinical problem and are the leading cause of death of SAA children. Active surveillance and the analysis of associated risk factors are required to detect opportunistic infections in this group of patients.

Prevalence, Epidemiology, Etiology, and Sensitivity of Invasive Bacterial Infections in Pediatric Patients Undergoing Oncological Treatment: A Multicenter Nationwide Study.

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.

Dysfunction of Salivary Glands, Disturbances in Salivary Antioxidants and Increased Oxidative Damage in Saliva of Overweight and Obese Adolescents.

Obesity is inseparably connected with oxidative stress. This process may disturb the functioning of the oral cavity, although the effect of oxidative stress on salivary gland function and changes in the qualitative composition of saliva are still unknown. Our study is the first to evaluate salivary redox homeostasis in 40 overweight and obese adolescents and in the age- and gender-matched control group. We demonstrated strengthening of the antioxidant barrier (superoxide dismutase, catalase, peroxidase, uric acid, total antioxidant capacity (TAC)) with a simultaneous decrease in reduced glutathione concentration in saliva (non-stimulated/stimulated) in overweight and obese teenagers compared to the controls. The concentration of the products of oxidative damage to proteins (advanced glycation end products), lipids (malondialdehyde, 4-hydroxynonenal) and DNA (8-hydroxydeoxyguanosine) as well as total oxidative status were significantly higher in both non-stimulated and stimulated saliva as well as plasma of overweight and obese adolescents. Importantly, we observed more severe salivary and plasma redox alterations in obese adolescents compared to overweight individuals. In the study group, we also noted a drop in stimulated salivary secretion and a decrease in total protein content. Interestingly, dysfunction of parotid glands in overweight and obese teenagers intensified with the increase of BMI. We also showed that the measurement of salivary catalase and TAC could be used to assess the central antioxidant status of overweight and obese adolescents.

Oral consequences of obesity and metabolic syndrome in children and adolescents.

Nowadays, the epidemic of obesity and metabolic syndrome can be observed not only among adults, but also amid the younger population, with more than 380 million children and adolescents worldwide being affected by these phenomena. Obesity is considered a systemic chronic metabolic disease resulting from the imbalance between energy intake and expenditure. The World Health Organization (WHO) has identified obesity as the most serious chronic disease, which, if untreated, leads to dangerous health problems (hypertension, heart failure, as well as kidney, nervous system and eye diseases). Recent scientific findings indicate a close relationship between obesity/metabolic syndrome and changes in the oral environment in children and adolescents. Obesity significantly increases the incidence of dental hard tissue diseases, periodontal diseases and diseases of the stomatognathic system. It also affects the secretion activity of the salivary glands, which changes the quantitative and qualitative composition of unstimulated and stimulated saliva. It is believed that in the face of a growing epidemic of obesity in children and adolescents, dental practitioners should also participate in the systemic treatment and prevention in this group of patients.

Low seroprevalence and low incidence of infection with Toxoplasma gondii (Nicolle et Manceaux, 1908) in pediatric hematopoietic cell transplantation donors and recipients: Polish nationwide study.

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.

Premature cyclosporine cessation and TBI-containing conditioning regimen increase the risk of acute GvHD in children undergoing unrelated donor hematopoietic stem cell transplantation.

BACKGROUND: Acute graft-versus-host disease (aGvHD) is a potentially fatal complication after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Identifying its risk factors would enable the proper prophylaxis and management, which may significantly improve the general outcome of children treated with HSCT. OBJECTIVES: The aim of this single-center, retrospective cohort study was to assess the potential risk factors for grades II-IV of aGvHD in children after the 1st allo-HSCT from an unrelated donor (UD), performed as a result of an underlying malignant disease. MATERIAL AND METHODS: From among patients who received HSCT in our center in the years 2004-2015, 237 were included in the study cohort. All the patients received standard aGvHD prophylaxis consisting of cyclosporine (CsA) and a short course of methotrexate (MTX). Various clinical and epidemiological features, the transplant proceedings, graft composition, conditioning regimens, as well as the duration and coherence of aGvHD prophylaxis were analyzed as potential risk factors for aGvHD. RESULTS: The incidence of II-IV aGvHD in the study cohort was 58.6%. The median time of the diagnosis of aGvHD was 18 days post-HSCT. In the multivariate analysis, risk factors significantly associated with grades II-IV of aGvHD were: myeloablative conditioning regimen containing total body irradiation (TBI-MAC) (RR (relative risk): 1.69; p = 0.03), premature termination of CsA administration due to its toxicity (RR: 1.99; p = 0.0003) and HSCT performed before the year 2009 (RR: 1.97; p = 0.0001). Donor and recipient age, donor-recipient sex mismatch, stem cell source, risk of disease, and amount of infused CD34+ cells seem to be insignificant as risk factors for aGvHD. The overall survival (OS) of patients with aGvHD was noticeably worse that in those who were aGvHD-free: 60.8% vs 74.1% (p = 0.08). CONCLUSIONS: The conditioning regimen and the proper aGvHD prophylaxis, including continuous CsA administration, have a major impact on aGvHD occurrence. According to our results, the termination of CsA therapy should be carefully considered, and avoided if possible.

Epidemiology, Outcome and Risk Factors Analysis of Viral Infections in Children and Adolescents Undergoing Hematopoietic Cell Transplantation: Antiviral Drugs Do Not Prevent Epstein-Barr Virus Reactivation.

OBJECTIVE: 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.

Infectious complications in children with malignant bone tumors: a multicenter nationwide study.

Objectives: 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.

Infections in children with acute myeloid leukemia: increased mortality in relapsed/refractory patients.

The aim of this nationwide study was to describe the epidemiology and profile of bacterial infections (BI), invasive fungal disease (IFD) and viral infections (VI) in patients with de novo and relapsed/refractory (rel/ref) acute myeloid leukemia (AML). Within the studied group of 250 children with primary AML, at least one infectious complication (IC) was diagnosed in 76.0% (n = 190) children including 85.1% (n = 504) episodes of BI, 8.3% (n = 49) - IFD and 6.6% (n = 39) - VI. Among 61 patients with rel/ref AML, at least one IC was found in 67.2% (n = 41) of children including 78.8% (n = 78) of BI, 14.1% (n = 14) of IFD and 7.1% (n = 7) of VI. In all AML patients, within BI Gram-negative strains were predominant. Half of these strains were multi-drug resistant. Characteristics of IFD and VI were comparable for de novo and rel/ref AML. The infection-related mortality was significantly higher, while survival from infection was significantly lower in patients with rel/ref disease.