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Risk factors for a severe disease course in children with SARS-COV-2 infection following hematopoietic cell transplantation in the pre-Omicron period: a prospective multinational Infectious Disease Working Party from the European Society for Blood and Marrow Transplantation group (EBMT) and the Spanish Group of Hematopoietic Stem Cell Transplantation (GETH) study
Averbuch, D., de la Camara, R., Tridello, G., Knelange, N. S., Bykova, T. A., Ifversen, M., Dobsinska, V., Ayas, M., Hamidieh, A. A., Pichler, H., et al
Bone marrow transplantation. 2023;:1-9
Abstract
Risk factors for severe SARS-Cov-2 infection course are poorly described in children following hematopoietic cell transplantation (HCT). In this international study, we analyzed factors associated with a severe course (intensive care unit (ICU) admission and/or mortality) in post-HCT children. Eighty-nine children (58% male; median age 9 years (min-max 1-18)) who received an allogeneic (85; 96%) or an autologous (4; 4%) HCT were reported from 28 centers (18 countries). Median time from HCT to SARS-Cov-2 infection was 7 months (min-max 0-181). The most common clinical manifestations included fever (37; 42%) and cough (26; 29%); 37 (42%) were asymptomatic. Nine (10%) children following allo-HCT required ICU care. Seven children (8%) following allo-HCT, died at a median of 22 days after SARS-Cov-2 diagnosis. In a univariate analysis, the probability of a severe disease course was higher in allo-HCT children with chronic GVHD, non-malignant disease, immune suppressive treatment (specifically, mycophenolate), moderate immunodeficiency score, low Lansky score, fever, cough, coinfection, pulmonary radiological findings, and high C-reactive protein. In conclusion, SARS-Cov-2 infection in children following HCT was frequently asymptomatic. Despite this, 10% needed ICU admission and 8% died in our cohort. Certain HCT, underlying disease, and SARS-Cov-2 related factors were associated with a severe disease course.
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Upper and/or lower respiratory tract infection caused by human metapneumovirus after allogeneic hematopoietic stem cell transplantation
Piñana, J. L., Tridello, G., Xhaard, A., Wendel, L., Montoro, J., Vazquez, L., Heras, I., Ljungman, P., Mikulska, M., Salmenniemi, U., et al
The Journal of infectious diseases. 2023
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Abstract
PATIENTS AND METHODS This retrospective multicenter cohort study examined the epidemiology, clinical characteristics, and risk factors for poor outcomes associated with human metapneumovirus (hMPV) infections in recipients of allogeneic stem cell transplantation (allo-HCT). RESULTS We included 428 allo-HCT recipients who developed 438 hMPV infection episodes between January 2012 and January 2019. Most recipients were adults (93%). hMPV infections were diagnosed at a median of 373 days after allo-HCT. The infections were categorized as upper respiratory tract disease (URTD) or lower respiratory tract disease (LRTD), with 60% and 40% of cases, respectively. Patients with hMPV LRTD experienced the infection earlier in the transplant course and had higher rates of lymphopenia, neutropenia, corticosteroid use, and ribavirin therapy. Multivariate analysis identified lymphopenia and corticosteroid use (>30 mg/d) as independent risk factors for LRTD occurrence. The overall mortality at day 30 after hMPV detection was 2% for URTD, 12% for possible LRTD, and 21% for proven LRTD. Lymphopenia was the only independent risk factor associated with day 30 mortality in LRTD cases. CONCLUSIONS These findings highlight the significance of lymphopenia and corticosteroid use in the development and severity of hMPV infections after allo-HCT, with lymphopenia being a predictor of higher mortality in LRTD cases.
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SARS-CoV-2 specific T-cells are generated in less than half of allogeneic HSCT recipients failing to seroconvert after COVID-19 vaccination
Jarisch, A., Wiercinska, E., Daqiq-Mirdad, S., Hellstern, H., Ajib, S., Cremer, A., Nguyen, N. T. T., Dukat, A., Ullrich, E., Ciesek, S., et al
European journal of immunology. 2022
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Reg3α levels at day of allogeneic stem cell transplantation predict outcome and correlate with early antibiotic use
Weber, D. A., Weber, M., Meedt, E., Ghimire, S., Wolff, D., Edinger, M., Poeck, H., Hiergeist, A., Gessner, A., Ayuk, F. A., et al
Blood advances. 2022
Abstract
The intestinal microbiome diversity plays an important role in the pathophysiology of acute gastrointestinal (GI) Graft-versus-Host Disease (aGvHD) and influences the outcome of patients after allogeneic stem cell transplantation (SCT). We analyzed clinical data and blood samples taken pre-conditioning and on the day of allogeneic SCT from 587 patients from seven German centers of the Mount Sinai Acute GvHD International Consortium (MAGIC), dividing them into a single-center test cohort (n=371) and a multicenter validation cohort (n=216). Reg3α serum concentration of day 0 correlated with clinical data as well as urinary 3-Indoxylsulfate and Clostridiales group XIVa, indicators of intestinal microbiome diversity. High Reg3α concentration at day 0 of allogeneic SCT was associated with higher 1-year transplant-related mortality (TRM) in both cohorts (p<0.001). Cox regression analysis revealed high Reg3α at day 0 as an independent prognostic factor for 1-year TRM (HR=2.9, 95%CI=1.8-4.8, p<0.001). Multivariable analysis showed an independent correlation of high Reg3α concentrations at day 0 and early systemic antibiotic treatment (OR=3.1, 95% CI = 2.0-4.8, p<0.001). Urinary 3-Indoxylsulfate (p=0.04) and Clostridiales group XIVa (p=0.004) were lower in patients with high Reg3α day 0 concentrations than in low Reg3α patients. In contrast, Reg3α concentrations prior to conditioning therapy correlated with neither TRM nor disease or treatment-related parameters. Reg3α, a known biomarker of acute GI GvHD correlates with intestinal dysbiosis induced by early antibiotic treatment in the period of pretransplant conditioning. Serum concentrations of Reg3α measured on the day of graft infusion are predictive of the risk for TRM of allogenic SCT recipients.
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Supportive care during pediatric hematopoietic stem cell transplantation: beyond infectious diseases. A report from workshops on supportive care of the Pediatric Diseases Working Party (PDWP) of the European Society for Blood and Marrow Transplantation (EBMT)
Nava, T., Ansari, M., Dalle, J. H., de Heredia, C. D., Gungor, T., Trigoso, E., Falkenberg, U., Bertaina, A., Gibson, B., Jarisch, A., et al
Bone marrow transplantation. 2020
Abstract
Hematopoietic stem cell transplantation (HSCT) is currently the standard of care for many malignant and nonmalignant blood diseases. As several treatment-emerging acute toxicities are expected, optimal supportive measurements critically affect HSCT outcomes. The paucity of good clinical studies in supportive practices gives rise to the establishment of heterogeneous guidelines across the different centers, which hampers direct clinical comparison in multicentric studies. Aiming to harmonize the supportive care provided during the pediatric HSCT in Europe, the Pediatric Diseases Working Party (PDWP) of the European Society for Blood and Marrow Transplantation (EBMT) promoted dedicated workshops during the years 2017 and 2018. The present paper describes the resulting consensus on the management of sinusoidal obstructive syndrome, mucositis, enteral and parenteral nutrition, iron overload, and emesis during HSCT.
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Prognostic impact of EBV serostatus in patients with lymphomas or chronic malignancies undergoing allogeneic HCT
Styczynski, J., Tridello, G., Gil, L., Ljungman, P., Mikulska, M., Ward, K. N., Cordonnier, C., de la Camara, R., Averbuch, D., Knelange, N., et al
Bone marrow transplantation. 2019
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Editor's Choice
Abstract
The influence of the donor (D) and recipient (R) pre-transplant Epstein-Barr Virus (EBV) serostatus on transplant outcomes (overall survival, relapse-free survival, relapse incidence, non-relapse mortality, acute and chronic GVHD) in 12,931 patients with lymphomas or chronic malignancies undergoing allogeneic hematopoietic cell transplant (allo-HCT) between 1997-2016 was analyzed. In multivariate analysis, the risk of development of chronic GVHD was increased for EBV R+/D+ (HR = 1.26; p = 0.003), R+/D- (HR = 1.21; p = 0.044), and R-/D + (HR = 1.21; p = 0.048) in comparison to R-/D- transplants. No significance was shown for other transplant outcomes; however, in univariate analysis, EBV-seropositive patients receiving grafts from EBV-seropositive donors (EBV R+/D+transplants) had inferior transplant outcomes in comparison to EBV-seronegative recipients of grafts from EBV-seronegative donors (EBV R-/D-): inferior overall survival (59.6% vs 65.9%), inferior relapse-free survival (51.1% vs 57.5%), increased incidence of chronic GVHD (49.5% vs 41.8%), and increased incidence of de novo chronic GVHD (30.5% vs 24.0%). In conclusion, an EBV-negative recipient with lymphoma or chronic malignancy can benefit from selection of an EBV-negative donor in context of chronic GVHD, while there are no preferences in donor EBV serostatus for EBV-seropositive recipient.
PICO Summary
Population
Patients with lymphomas or chronic malignancies undergoing allogeneic hematopoietic cell transplant between 1997-2016 (n=12,931)
Intervention
Epstein-Barr virus seropositive donors (D+) and/or recipients (R+)
Comparison
Epstein-Barr virus seronegative donors (D-) and/or recipients (R-)
Outcome
In multivariate analysis, the risk of development of chronic GVHD was increased for EBV R+/D+, R+/D- and R-/D + in comparison to R-/D- transplants. No significance was shown for other transplant outcomes; however, in univariate analysis, EBV-seropositive patients receiving grafts from EBV-seropositive donors (EBV R+/D+transplants) had inferior transplant outcomes in comparison to EBV-seronegative recipients of grafts from EBV-seronegative donors (EBV R-/D-): inferior overall survival (59.6% vs 65.9%), inferior relapse-free survival (51.1% vs 57.5%), increased incidence of chronic GVHD (49.5% vs 41.8%), and increased incidence of de novo chronic GVHD (30.5% vs 24.0%).
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Allogeneic hematopoietic stem cell transplantation from unrelated donors is associated with higher infection rates in children with acute lymphoblastic leukemia - A prospective international multicenter trial on behalf of the BFM-SG and the EBMT-PDWP
Pichler, H., Lawitschka, A., Glogova, E., Willasch, A. M., von Luettichau, I., Lehrnbecher, T., Matthes-Martin, S., Lang, P., Bader, P., Sykora, K. W., et al
American journal of hematology. 2019
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Editor's Choice
Abstract
Severe infections (SI) significantly impact on non-relapse mortality after hematopoietic stem cell transplantation (HSCT). We assessed 432 children and adolescents with acute lymphoblastic leukemia (ALL) after total body irradiation based myeloablative HSCT within the multicenter ALL-BFM-SCT 2003 trial for SI grade 3 or higher according to common terminology criteria for adverse events. A total 172 patients experienced at least one SI. Transplantation from matched unrelated donors (MUD) was associated with any type of SI in the pre-engraftment period (hazard ratio [HR]: 2.57; P < 0.001) and with any SI between day +30 and + 100 (HR: 2.91; P = 0.011). Bacterial (HR: 2.24; P = 0.041) and fungal infections (HR: 4.06; P = 0.057) occurred more often in the pre-engraftment phase and viral infections more often before day +30 (HR: 2.66; P = 0.007) or between day +30 and + 100 (HR: 3.89; P = 0.002) after HSCT from MUD as compared to matched sibling donors. Chronic GvHD was an independent risk factor for any type of SI after day +100 (HR: 2.57; P < 0.002). We conclude that allogeneic HSCT from MUD in children and adolescents with pediatric ALL is associated with higher infection rates, which seems attributable to an intensified GvHD prophylaxis including serotherapy and methotrexate.
PICO Summary
Population
Children and adolescents with acute lymphoblastic leukemia (n=432)
Intervention
Total body irradiation based myeloablative HSCT
Comparison
None
Outcome
A total 172 patients experienced at least one severe infection (SI). Transplantation from matched unrelated donors (MUD) was associated with any type of SI in the pre-engraftment period and with any SI between day +30 and + 100. Bacterial and fungal infections occurred more often in the pre-engraftment phase and viral infections more often before day +30 or between day +30 and + 100 after HSCT from MUD as compared to matched sibling donors. Chronic GvHD was an independent risk factor for any type of SI after day +100.