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sVEGF-R1 in acute non-infectious toxicity syndromes after pediatric allogeneic hematopoietic stem cell transplantation
Horan, D. E., Kielsen, K., Weischendorff, S. W., Sørum, M. E., Kammersgaard, M. B., Ifversen, M., Nielsen, C., Ryder, L. P., Johansson, P. I., Müller, K.
Transplant immunology. 2023;82:101975
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Abstract
BACKGROUND Allogeneic hematopoietic stem cell transplantation (HSCT) is challenged by acute non-infectious toxicities, including sinusoidal obstruction syndrome (SOS), engraftment syndrome (ES) and capillary leak syndrome (CLS) among others. These complications are thought to be driven by a dysfunctional vascular endothelium, but the pathophysiological mechanisms remain incompletely understood, and the diagnoses are challenged by purely clinical diagnostic criteria that are partly overlapping, limiting the possibilities for progress in this field. There is, however, increasing evidence suggesting that these challenges may be met through the development of diagnostic biomarkers to improve diagnostic accuracy of pathogenetically homogenous entities, improved pre-transplant risk assessment and the early identification of patients with increased need for specific treatment. Soluble vascular endothelial growth factor receptor-1 (sVEGF-R1) is emerging as an important biomarker of endothelial damage in patients with trauma and sepsis but has not been studied in HSCT. OBJECTIVES To investigate sVEGF-R1 as a marker of endothelial damage in pediatric HSCT patients by exploring associations with SOS, CLS, ES, and acute graft-versus-host disease (aGvHD). METHODS We prospectively included 113 children undergoing myeloablative HSCT and measured sVEGF-R1 in plasma samples obtained weekly during the early period of transplantation and 3 months post-transplant. RESULTS All over, sVEGF-R1 levels were significantly increased from day +7 after graft infusion, peaking at day +30, most pronounced in patients receiving busulfan. Patients considered to be at increased risk of SOS and therefore commenced on prophylactic defibrotide had significantly elevated levels of sVEGF-R1 before start of conditioning (446 pg/mL vs. 281 pg/mL, p = 0.0035), and this treatment appeared to stabilize sVEGF-R1 levels compared to patients not treated with defibrotide. Thirteen (11.5%) children meeting the modified Seattle criteria for SOS at median day +8 (1-18), had significantly elevated sVEGF-R1 levels on day +14 (489 pg/mL vs. 327 pg/mL, p = 0.007). In contrast. sVEGF-R1 levels in the much broader group of patients (45.1%) meeting EBMT-SOS criteria, including patients with very mild disease, did not overall differ in sVEGF-R1 levels, but higher sVEGF-R1 levels were seen in EBMT-SOS patients with an increased need for diuretic treatment. Importantly, sVEGF-R1 levels were not associated with ES and CLS but were significantly increased on day +30 in patients with grade III-IV aGvHD (OR = 4.2 pr. quartile, p = 0.023). CONCLUSION VEGF-R1 levels are found to be increased in pediatric patients developing SOS, reflecting the severity of morbidity. sVEGF-R1 were unassociated with both CLS and ES. The potential of sVEGF-R1 as a clinically useful biomarker for SOS should be further explored to improve pre-transplant SOS-risk assessment, SOS-severity grading, and to guide treatment.
PICO Summary
Population
We prospectively included 113 children undergoing myeloablative HSCT
Intervention
Measurement of sVEGF-R1 in plasma samples obtained weekly during the early period of transplantation and 3 months post-transplant to explore associations with sinusoidal obstruction syndrome (SOS), capillary leak syndrome (CLS), engraftment syndrome (ES), and acute graft-versus-host disease (aGvHD)
Comparison
None
Outcome
All over, sVEGF-R1 levels were significantly increased from day +7 after graft infusion, peaking at day +30, most pronounced in patients receiving busulfan. Patients considered to be at increased risk of SOS and therefore commenced on prophylactic defibrotide had significantly elevated levels of sVEGF-R1 before start of conditioning (446 pg/mL vs. 281 pg/mL), and this treatment appeared to stabilize sVEGF-R1 levels compared to patients not treated with defibrotide. Thirteen (11.5%) children meeting the modified Seattle criteria for SOS at median day +8 (1-18), had significantly elevated sVEGF-R1 levels on day +14 (489 pg/mL vs. 327 pg/mL). In contrast. sVEGF-R1 levels in the much broader group of patients (45.1%) meeting EBMT-SOS criteria, including patients with very mild disease, did not overall differ in sVEGF-R1 levels, but higher sVEGF-R1 levels were seen in EBMT-SOS patients with an increased need for diuretic treatment. Importantly, sVEGF-R1 levels were not associated with ES and CLS but were significantly increased on day +30 in patients with grade III-IV aGvHD (OR = 4.2 pr. quartile).
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Plasma levels of MRP-8/14 associate with neutrophil recovery, bacterial bloodstream infections and engraftment syndrome following pediatric allogeneic hematopoietic stem cell transplantation
Kammersgaard, M. B., Kielsen, K., Nielsen, C. H., Ifversen, M., Bohr, A. H., Müller, K.
Transplantation and cellular therapy. 2022
Abstract
BACKGROUND Neutrophil engraftment is essential for successful outcome after allogeneic hematopoietic stem cell transplantation (HSCT), but neutrophil activation may also induce transplant-related complications. Myeloid-related protein (MRP)-8/14 is expressed in granulocytes during inflammatory conditions and secreted in response to tissue damage along with the release of pro-inflammatory cytokines together with leukocyte recruitment and activation. OBJECTIVE In this study, we investigated associations between levels of the neutrophil activity marker MRP-8/14, neutrophil recovery and toxicities after pediatric HSCT. STUDY DESIGN We included 73 children undergoing allogeneic HSCT using bone marrow or peripheral blood stem cell grafts from matched sibling or unrelated donors. Plasma levels of MRP-8/14 were measured by ELISA from pre-conditioning until six months post-transplant. RESULTS Overall, MRP-8/14 levels decreased from pre-conditioning to a nadir at day +7 and then rose again until day +28, preceding the reappearance of neutrophils. MRP-8/14 levels were significantly reduced at day +14 in patients with delayed neutrophil engraftment compared with patients who engrafted by day +21 (0.20 vs. 0.48 μg/mL, P=0.0012) and in patients who developed bacterial bloodstream infections compared to patients without this complication (0.2 vs. 0.36 μg/mL, P=0.048). Patients developing engraftment syndrome had significantly elevated MRP-8/14 levels at day +7 and +21 compared to patients without engraftment syndrome (0.32 vs. 0.2 μg/mL, P=0.042 and 1.9 vs. 0.80 μg/mL, P=0.039, respectively) as well as increased neutrophil counts from day +9 to +25 (P≤0.016). Similarly, neutrophil counts were increased at day +13 to +17 in patients with acute graft-versus-host disease grade III-IV compared with grade 0-II. CONCLUSION This study is the first to monitor neutrophil activation by MRP-8/14 in HSCT patients in relation to infectious as well as non-infectious post-transplant complications. Our results provide increased insights into the pathophysiology of these complications and further studies should explore the potential use of MRP-8/14 as a clinically useful biomarker.
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Declining mortality rates in children admitted to ICU following HCT
Jensen, M. L. N., Nielsen, J. S. A., Nielsen, J., Lundstrøm, K. E., Heilmann, C., Ifversen, M.
Pediatric transplantation. 2020;:e13946
Abstract
We aimed to assess short- and long-term mortality, including factors associated with mortality, for children referred to a pediatric intensive care unit (ICU) at Rigshospitalet, Denmark, following haematopoietic cell transplantation (HCT). Data regarding admission to ICU and mortality following HCT for children below 16 years of age between 2000 and 2017 were retrospectively analyzed. We identified 55 ICU admissions in 39 patients following 46 HCTs. The overall in-ICU, in-hospital, 3-month, and 1-year mortality rates were 33.3%, 43.6%, 46.2%, and 51.3%, respectively. Patients admitted from 2000 to 2010 had a 3-month mortality of 63.2% and 1-year mortality of 68.4%, compared to 30% and 35% (P = .040 and P = .039) for patients admitted from 2011 to 2017. The main reason for ICU admission was respiratory failure (78.2%). Mechanical ventilation (MV) was associated with a higher long-term mortality (P = .044), and use of inotropes or vasopressors was associated with increased mortality at all times (all P > .006). Extracorporeal life support, renal replacement therapy, longer ICU stay, and longer time with MV were not associated with increased mortality. Over the past two decades, mortality was significantly reduced in pediatric HCT patients admitted to the ICU. The cause is probably multifactorial and warrants further studies. Our findings support admissions of critically ill pediatric HCT patients to intensive care with encouraging outcomes of even long-term admissions.
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Low incidence of hemorrhagic cystitis following ex vivo T-cell depleted haploidentical hematopoietic cell transplantation in children
Jepsen, C., Turkiewicz, D., Ifversen, M., Heilmann, C., Toporski, J., Dykes, J., Mellgren, K., Jan Pronk, C.
Bone marrow transplantation. 2019
Abstract
Hemorrhagic cystitis (HC) is a debilitating complication following allogenic hematopoietic cell transplantation (HCT). HLA disparity and T-cell depletion have been implicated as risk factors for HC. However, reports on the incidence and risk factors for HC in ex vivo T-cell depleted haploidentical HCT (haploHCT) in children are lacking. We studied 96 haploHCT procedures performed in 83 children between 2002 and 2017. Sixty-three patients were diagnosed with a malignant disease and 20 with nonmalignant disease. All but three patients with SCID underwent myelotoxic and/or lymphotoxic conditioning therapy. Grafts were CD3+ (36.5%) or TcRalphabeta+ (63.5%) depleted to prevent graft versus host disease (GvHD). Fourteen patients (14.6%) were diagnosed with HC; 12 (12.5%) had clinically significant stage II-IV HC. All patients with HC had BK viruria and/or viremia. Increasing age and chemotherapeutic treatment prior to conditioning were identified as risk factors for HC. Immune recovery did not significantly differ between patients with and without HC. Thus, we report a low incidence of HC in pediatric haploHCT using ex vivo T-cell depletion. The combination of a reduced toxicity conditioning regimen, and typically absent pharmaceutical post-HCT GvHD prophylaxis in our patients might have contributed to the decreased the risk of HC, despite HLA disparity.
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Assessment of the proposed EBMT pediatric criteria for diagnosis and severity grading of sinusoidal obstruction syndrome
Kammersgaard, M. B., Kielsen, K., Heilmann, C., Ifversen, M., Muller, K.
Bone marrow transplantation. 2019
Abstract
Sinusoidal obstruction syndrome (SOS) is a potentially life-threatening complication of allogeneic hematopoietic stem cell transplantation (HSCT). We assessed the proposed pediatric EBMT criteria along with the Baltimore and modified Seattle criteria in a population-based cohort. Eighty-seven children (1.1-17.3 years) undergoing myeloablative HSCT from 2010 to 2017 were consecutively included at the Danish National Transplantation Center. In total, 39 (44.8%) patients fulfilled the EBMT criteria and 30 patients (35%) fulfilled the criteria for severe or very severe SOS. Nine (10.3%) patients fulfilled the modified Seattle criteria while none met the Baltimore criteria. Patients fulfilling the EBMT criteria for SOS had longer primary admission (31 days (23-183) vs. 27 days (17-61), p = 0.001), were treated more intensively with diuretics within the first 3 months (29 days (0-90) vs. 3.5 days (0-90), p < 0.0001), and had a longer time to stable platelet counts >50 x 10(9)/L (32 days (16-183) vs. 23 days (14-101), p < 0.0001). Two patients, fulfilling neither Baltimore nor Seattle criteria, but selectively fulfilling EBMT criteria, died of treatment-related acute inflammatory complications within 1 year post-HSCT. In conclusion, application of the pediatric EBMT diagnostic and severity criteria may be helpful in identifying patients at increased risk of severe treatment-related complications and mortality, although with a risk of over-diagnosing SOS.