Publications by authors named "Carsten Heilmann"

79 Publications

Concentrations of tetanus and diphtheria antibodies in vaccinated Greenlandic children aged 7-12 years exposed to marine pollutants, a cross sectional study.

Environ Res 2021 Jul 31;203:111712. Epub 2021 Jul 31.

Department of Environmental Medicine, University of Southern Denmark, Odense, Denmark; Department of Environmental Health, Harvard T.H. Chan School of Public Health, Boston, MA, USA.

Previous studies have shown immunotoxic effects of environmental chemicals, and the European Food Safety Authority (EFSA) recently identified a need for more studies on PFAS immunotoxicity in different populations. In the Arctic, populations are exposed to several environmental chemicals through marine diet, and the objective of this study was therefore to examine the association between Greenlandic children's exposure to major environmental chemicals and their concentrations of diphtheria and tetanus vaccine antibodies after vaccination. The study includes cross-sectional data from Greenlandic children aged 7-12 years examined during 2012-2015. A total of 338 children were eligible for the study, and 175 of these had available vaccination records. A parent or guardian participated in a structured interview, and a blood sample from the child was analyzed for specific antibodies against diphtheria and tetanus as well as perfluoroalkyl substances (PFASs), polychlorinated biphenyls (PCBs) and total mercury. Furthermore, for a subgroup, blood samples from pregnancy were available and analyzed for environmental contaminants. The associations between the environmental exposures and antibody concentrations and odds of having antibody concentrations below the protective level were examined in linear and logistic regression models. In crude analyses, elevated concentrations of some of the contaminants were associated with higher concentrations of diphtheria and tetanus antibodies, but the associations were reversed when adjusting for area of residence, and duration of being breastfed and including children with a known vaccination date only. Each 1 ng/mL increase in serum concentrations of perfluorohexane sulfonic acid (PFHxS) and perfluorooctane sulfonic acid (PFOS) was associated with decreases of 78 % (95 % CI: 25-94 %) and 9 % (95 % CI: 2-16 %), respectively, in diphtheria antibody concentrations. Exposure to PCBs and all PFASs was associated with markedly increased odds of having diphtheria antibody concentrations below the protective level. For each 1 ng/mL increase in serum concentrations of PFHxS, PFOS, perfluorononanoic acid (PFNA), and perfluorodecanoic acid (PFDA), odds of not having protective levels of diphtheria antibodies were increased 6.44 times (95 % CI: 1.51-27.36), 1.14 times (95 % CI: 1.04-1.26), 1.96 times (95 % CI: 1.07-3.60), and 5.08 times (95 % CI: 1.32-19.51, respectively. No consistent associations were seen between maternal contaminant concentrations and vaccine antibody concentrations. In conclusion, we found that increased exposure to environmental chemicals among children in this Arctic population were associated with a decrease in post-vaccination antibody concentrations and with increased odds of not being protected against diphtheria despite appropriate vaccination. These findings emphasize the risk of environmental chemical exposures also in this Arctic population.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.envres.2021.111712DOI Listing
July 2021

Serum vaccine antibody concentrations in adults exposed to per- and polyfluoroalkyl substances: A birth cohort in the Faroe Islands.

J Immunotoxicol 2021 12;18(1):85-92

Department of Environmental Health, Harvard T. H. Chan School of Public Health, Cambridge, MA, USA.

Per- and polyfluoroalkyl substances (PFASs) are highly persistent in the environment and may cause depressed immune function. Previous studies have linked PFAS exposure to lower vaccine responses in children, but research in adults is limited. Therefore, the present study evaluated the associations between exposure to PFASs and serum antibody concentrations in adults vaccinated at age 28 years in the Faroe Islands. PFAS concentrations were determined from cord-blood collected at birth and serum samples collected at ages 7, 14, 22, and 28 years. Serum antibody concentrations against hepatitis type A and B, diphtheria, and tetanus were analyzed from blood samples collected about 6 mo after the first vaccine inoculation at age 28 years. Linear regression models were used to estimate changes in antibody concentration for each doubling of PFAS concentration. Potential effect modification by sex was assessed by including an interaction term between PFAS and sex. Although the 95% confidence intervals contain the null value, inverse trends were observed between serum perfluorooctanoate (PFOA) at ages 14 and 28 years and hepatitis type A antibody (anti-HAV) concentrations, as revealed by an estimated decrease of 0.71 (95% CI: -1.52, 0.09) and 0.24 (95% CI: -0.59, 0.10) signal-to-cutoff ratio for each doubling of exposure, respectively. Inverse trends were also observed between serum PFOA at ages 22 and 28 years and hepatitis type B antibody (anti-HBs) concentration, with an estimated decrease of 21% (95% CI: -42.20%, 7.34%) and of 17% (95% CI: -35.47%, 7.35%) in anti-HBs for each doubling of exposure, respectively. Sex-specific associations with anti-HAV were observed for cord-blood PFASs and serum PFAS concentrations at ages 7 and 14 years. No inverse associations of PFAS exposure were found with diphtheria and tetanus antibody concentrations. Future studies are needed to confirm these findings and further investigate the effects of PFASs on adult immune function.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1080/1547691X.2021.1922957DOI Listing
December 2021

IL-7 and IL-15 Levels Reflect the Degree of T Cell Depletion during Lymphopenia and Are Associated with an Expansion of Effector Memory T Cells after Pediatric Hematopoietic Stem Cell Transplantation.

J Immunol 2021 Jun 9. Epub 2021 Jun 9.

Hematopoietic Stem Cell Transplantation and Primary Immune Deficiency, Department of Pediatrics and Adolescent Medicine, Copenhagen University Hospital Rigshospitalet, Copenhagen, Denmark.

Differentially and functionally distinct T cell subsets are involved in the development of complications after allogeneic hematopoietic stem cell transplantation (HSCT), but little is known about factors regulating their recovery after HSCT. In this study, we investigated associations between immune-regulating cytokines, T cell differentiation, and clinical outcomes. We included 80 children undergoing allogeneic HSCT for acute leukemia using bone marrow or peripheral blood stem cells grafted from a matched sibling or unrelated donor. Cytokines (IL-7, IL-15, IL-18, SCF, IL-6, IL-2, and TNF-α) and active anti-thymocyte globulin (ATG) levels were longitudinally measured along with extended T cell phenotyping. The cytokine profiles showed a temporary rise in IL-7 and IL-15 during lymphopenia, which was strongly dependent on exposure to active ATG. High levels of IL-7 and IL-15 from graft infusion to day +30 were predictive of slower T cell recovery during the first 2 mo post-HSCT; however, because of a major expansion of memory T cell stages, only naive T cells remained decreased after 3 mo ( < 0.05). No differential effect was seen on polarization of CD4 T cells into Th1, Th2, or Th17 cells or regulatory T cells. Low levels of IL-7 and IL-15 at day +14 were associated with acute graft-versus-host disease grades II-IV in ATG-treated patients ( = 0.0004 and = 0.0002, respectively). Children with IL-7 levels comparable to healthy controls at day +14 post-HSCT were less likely to develop EBV reactivation posttransplant. These findings suggest that quantification of IL-7 and IL-15 may be useful as biomarkers in assessing the overall T cell depletion and suggest a potential for predicting complications after HSCT.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.4049/jimmunol.2001077DOI Listing
June 2021

Allogeneic hematopoietic stem cell transplantation in leukocyte adhesion deficiency type I and III.

Blood Adv 2021 01;5(1):262-273

Pediatric Hematology, Ankara Child Health and Diseases Hematology Oncology Training and Research Hospital, Ankara, Turkey.

Type I and III leukocyte adhesion deficiencies (LADs) are primary immunodeficiency disorders resulting in early death due to infections and additional bleeding tendency in LAD-III. The curative treatment of LAD-I and LAD-III is allogeneic hematopoietic stem cell transplantation (allo-HSCT). In this retrospective multicenter study, data were collected using the European Society for Blood and Marrow Transplantation registry; we analyzed data from 84 LAD patients from 33 centers, all receiving an allo-HSCT from 2007 to 2017. The 3-year overall survival estimate (95% confidence interval [CI]) was 83% (74-92) for the entire cohort: 84% (75-94) and 75% (50-100) for LAD-I and LAD-III, respectively. We observed cumulative incidences (95% CI) of graft failure (GF) at 3 years of 17% (9%-26%) and grade II to IV acute graft-versus-host disease (aGVHD) at 100 days of 24% (15%-34%). The estimate (95% CI) at 3 years for GF- and GVHD-II to IV-free survival as event-free survival (EFS) was 56% (46-69) for the entire cohort; 58% (46-72) and 56% (23-88) for LAD-I and LAD-III, respectively. Grade II to IV acute GVHD was a relevant risk factor for death (hazard ratio 3.6; 95% CI 1.4-9.1; P = .006). Patients' age at transplant ≥13 months, transplantation from a nonsibling donor, and any serological cytomegalovirus mismatch in donor-recipient pairs were significantly associated with severe acute GVHD and inferior EFS. The choice of busulfan- or treosulfan-based conditioning, type of GVHD prophylaxis, and serotherapy did not impact overall survival, EFS, or aGVHD. An intrinsic inflammatory component of LAD may contribute to inflammatory complications during allo-HSCT, thus providing the rationale for considering anti-inflammatory therapy pretreatment.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1182/bloodadvances.2020002185DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7805328PMC
January 2021

High preharvest donor Foxp3 mRNA level predicts late relapse of acute lymphoblastic leukaemia after haematopoietic stem cell transplantation.

Eur J Haematol 2021 May 15;106(5):643-653. Epub 2021 Feb 15.

Department of Clinical Immunology, Tissue Typing Laboratory, Rigshospitalet University Hospital, Copenhagen, Denmark.

Objectives: The curative effect of allogeneic haematopoietic stem cell transplantation (HSCT) for acute leukaemia is due in part to the donor T cell-mediated graft-versus-leukaemia immune reaction (GvL). Several studies have suggested that donor CD25+CD4+Foxp3+regulator T cells (Tregs) may decrease graft-versus-host disease (GvHD) without abrogating GVL. This notion may need modification in acute lymphoblastic leukaemia (ALL).

Methods: Foxp3 mRNA level was measured by qPCR in preharvest donor blood CD4+ T cells. The study comprised 45 patients with ALL in 1st or 2nd CR who received myeloablative HSCT using T-replete bone marrow grafts.

Results: Relapse occurred in 17 patients median 363 days after HSCT. The relapse risk was estimated by Cox univariate and multivariate proportional hazard regression. The proportionality assumption was met by analysing the preharvest donor Foxp3 mRNA level as a time-dependent covariate. Early relapse was not modified by the Foxp3 mRNA level. However, a higher Foxp3 mRNA level was associated with a significantly increased relapse risk after day 363 after transplantation, compatible with inhibition of GvL. In contrast, a higher preharvest donor CD4+ T-cell concentration was associated with reduced relapse risk.

Conclusion: A higher preharvest donor Foxp3 mRNA level may be predictive of late ALL relapse after HSCT.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/ejh.13591DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8248440PMC
May 2021

Severity of COVID-19 at elevated exposure to perfluorinated alkylates.

PLoS One 2020 31;15(12):e0244815. Epub 2020 Dec 31.

The Department of Epidemiology, Statens Serum Institut, Copenhagen, Denmark.

Background: The course of coronavirus disease 2019 (COVID-19) seems to be aggravated by air pollution, and some industrial chemicals, such as the perfluorinated alkylate substances (PFASs), are immunotoxic and may contribute to an association with disease severity.

Methods: From Danish biobanks, we obtained plasma samples from 323 subjects aged 30-70 years with known SARS-CoV-2 infection. The PFAS concentrations measured at the background exposures included five PFASs known to be immunotoxic. Register data was obtained to classify disease status, other health information, and demographic variables. We used ordered logistic regression analyses to determine associations between PFAS concentrations and disease outcome.

Results: Plasma-PFAS concentrations were higher in males, in subjects with Western European background, and tended to increase with age, but were not associated with the presence of chronic disease. Of the study population, 108 (33%) had not been hospitalized, and of those hospitalized, 53 (16%) had been in intensive care or were deceased. Among the five PFASs considered, perfluorobutanoic acid (PFBA) showed an unadjusted odds ratio (OR) of 2.19 (95% confidence interval, CI, 1.39-3.46) for increasing severities of the disease. Among those hospitalized, the fully adjusted OR for getting into intensive care or expiring was 5.18 (1.29, 20.72) when based on plasma samples obtained at the time of diagnosis or up to one week before.

Conclusions: Measures of individual exposures to immunotoxic PFASs included short-chain PFBA known to accumulate in the lungs. Elevated plasma-PFBA concentrations were associated with an increased risk of a more severe course of COVID-19. Given the low background exposure levels in this study, the role of exposure to PFASs in COVID-19 needs to be ascertained in populations with elevated exposures.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0244815PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7774856PMC
January 2021

Declining mortality rates in children admitted to ICU following HCT.

Pediatr Transplant 2021 Aug 12;25(5):e13946. Epub 2020 Dec 12.

Department of Paediatrics and Adolescent Medicine, Bone Marrow Transplant Unit, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark.

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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/petr.13946DOI Listing
August 2021

Vitamin D levels and busulphan kinetics in patients undergoing hematopoietic stem cell transplantation, a multicenter study.

Bone Marrow Transplant 2021 04 21;56(4):807-817. Epub 2020 Oct 21.

Experimental Cancer Medicine, Division of Clinical Research Center, Department of Laboratory Medicine, Karolinska Institutet, Stockholm, Sweden.

Vitamin D (Vit-D), an essential nutrient, interacts with different drugs including chemotherapeutic agents like busulphan, an alkylating agent used for conditioning prior to stem cell transplantation. The correlation between Vit-D plasma levels and busulphan clearance was investigated in an uncontrolled prospective study in patients and mice. Plasma 25(OH)D levels were measured and busulphan pharmacokinetics calculated in 81 patients. Adults received oral busulphan (n = 34) while children received busulphan orally (n = 19) or intravenously (n = 28). Patients received no Vit-D supplementation. To confirm our findings, pharmacokinetics after a single dose of busulphan (oral or intravenous) were evaluated in two groups of mice (n = 60) receiving high or standard-level Vit-D supplementation. Both busulphan clearance (P < 0.0001) and 25(OH)D levels (P = 0.0004) were significantly higher in adults compared to children. A significant negative correlation (P = 0.041) was found between busulphan clearance and 25(OH)D levels in children treated orally. No such correlation was observed in adults or in children receiving intravenous busulphan. In addition, no significant effect of Vit-D levels on busulphan pharmacokinetics in mice regardless of the administration route. In conclusion, 25(OH)D can affect oral busulphan pharmacokinetics in children and its level should be considered when personalizing oral busulphan treatment. Further studies are warranted to confirm the underlying mechanisms.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41409-020-01091-yDOI Listing
April 2021

Insulin-Like Growth Factor Gene Polymorphisms Predict Clinical Course in Allogeneic Hematopoietic Stem Cell Transplantation.

Front Immunol 2020 24;11:1646. Epub 2020 Jul 24.

Department of Pediatrics and Adolescent Medicine, University Hospital Rigshospitalet, Copenhagen, Denmark.

Allogeneic hematopoietic stem cell transplantation (HSCT) is challenged by significant toxicities that are propagated by systemic inflammation caused by cytotoxic damage. Insulin-like growth factor-1 (IGF-1) is key in repair of most tissues and is to a large extent genetically determined. We investigated eight single nucleotide polymorphisms (SNPs) in the genes encoding IGF-1 and its binding protein (IGFBP3) in 543 patients undergoing HSCT to access their impact on systemic inflammation and clinical outcomes. Overall, median serum levels of both IGF-1 and IGFBP3 were found reduced from the referral until 2 years post-HSCT compared with healthy sex- and age-matched individuals, but, for individuals homozygous of the known high-producer minor allele of rs1520220 (), rs978458 (), or rs2854744 () serum levels remained normal during the whole period. In accordance, maximum C-reactive protein levels were lower for these genotypes of (rs1520220: median 66 vs. 102 mg/L, = 0.005 and rs978458: 53 vs. 104 mg/L, < 0.001), translating into borderline significant superior survival ( = 0.060 for rs1520220) and reduced treatment-related mortality ( = 0.050 for rs978458). In conclusion, we found that three SNPs in the IGF-1 axis with known functional impact were associated with circulating IGF-1 or IGFBP-3 levels also in the setting of HSCT, and predictive of the severity of the toxic-inflammatory response during the treatment.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fimmu.2020.01646DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7393983PMC
April 2021

Is microchimerism a sign of imminent disease recurrence after allogeneic hematopoietic stem cell transplantation? A systematic review of the literature.

Blood Rev 2020 11 26;44:100673. Epub 2020 Feb 26.

Pediatric Stem Cell Transplant and Immune Deficiency, Department for Children and Adolescents, Rigshospitalet, University Hospital of Copenhagen, Copenhagen, Denmark. Electronic address:

Chimerism analysis following hematopoietic stem cell transplantation (HSCT) for leukemia is routinely applied in parallel with quantification of minimal residual disease (MRD) to identify imminent relapse. In the past decades, new methods with a lower limit of detection compared to standard methods have been developed, so-called microchimerism analysis. Microchimerism analysis is fast, simple, applicable across pre-HSCT disease-type and can be applied on peripheral blood allowing frequent testing during follow-up. Monitoring of microchimerism in blood could replace repeated bone marrow analysis for MRD and allow earlier detection of imminent relapse or graft failure. Clinical studies in single center cohorts have shown conflicting but promising results. There is currently no consensus on the interpretation of microchimerism analysis and heterogeneity of studies remains a major obstacle for inter-study comparisons and meta-analysis in this field. We have conducted a systematic review of studies investigating associations between microchimerism and relapse of leukemia post-HSCT. We summarize current evidence and provide suggestions for future research.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.blre.2020.100673DOI Listing
November 2020

Depletion of αβ+ T and B Cells Using the CliniMACS Prodigy: Results of 10 Graft-Processing Procedures from Haploidentical Donors.

Transfus Med Hemother 2019 Dec 7;46(6):446-449. Epub 2019 Mar 7.

The Cell Therapy Facility, Department of Clinical Immunology, Rigshospitalet Copenhagen University Hospital, Copenhagen, Denmark.

Background: Depletion of TCRαβ+ T cells and B cells with the CliniMACS Plus® has been used for haploidentical hematopoietic stem cell transplantation for a decade. The depletion procedure is time and labour demanding and with variable reported efficiencies. Recently, an automated procedure was launched for the CliniMACS Prodigy® (Miltenyi Biotec) but reported data are scarce. Here, we report the results of the first ten TCRαβ+ and B cell depletion procedures for clinical use performed at our centre.

Materials And Methods: All transplants were from a parent to a child. Collection of peripheral blood stem cells was performed after filgrastim mobilisation by use of the Spectra Optia® (TerumoBCT) set on the MNC program. Because of insufficient hematopoietic stem cell mobilisation, 1 donor received additional plerixafor.

Results: We performed ten uncomplicated processes with the CliniMACS Prodigy. We found the results of the depletion procedures satisfactory with a median log reduction of TCRαβ+ cells of -4.21 (range -3.98 to -4.74), resulting in a median number of TCRαβ+ cells in the depleted product of 28.6 × 103/kg recipient weight (range 14.9-69.7 × 103/kg). The median CD34 recovery was 83% (range 70-100). To achieve a sufficient number of CD34+ cells, we performed an additional CD34+ enrichment procedure using the CliniMACS Plus for 3 patients. The B cell depletion was slightly less efficient with a median log reduction of -3.72 (range -2.83 to -4.20).

Conclusion: Overall, we found the TCRαβ and CD19 depletion procedure on the CliniMACS Prodigy easy to handle and reliable, providing reproducible good results.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1159/000497074DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6944939PMC
December 2019

Antibody response to vaccination after haematopoietic cell transplantation in children using a reduced dose schedule-A retrospective cohort study.

Pediatr Transplant 2020 02 16;24(1):e13599. Epub 2019 Oct 16.

The Department of Paediatrics and Adolescent Medicine, Juliane Marie Centre, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark.

Children receiving HCT loose protective immunity to vaccines received pre-HCT. Therefore, revaccination post-HCT is of major importance. In Denmark, a vaccination schedule with fewer doses post-HCT has been used, including two doses for diphtheria, tetanus, polio, measles, mumps, and rubella, and one dose only for Haemophilus influenzae type B. The background for this was the presumption that post-HCT immunization constituted booster vaccination of donor immunity. Our objective was to evaluate the proportion of children protected after the scheduled vaccination programme. A nationwide retrospective cohort study of all children who have received an HCT in Denmark during 1994-2012. Antibody levels were analysed in blood samples drawn before and after vaccination, and the probability of achieving protection after the scheduled immunization programme was estimated. A total of 198 children were included. The protection post-immunization was as follows: diphtheria 75.3%, tetanus 89.1%, polio 97.7%, and Haemophilus influenzae type B 94.8%. For diphtheria and tetanus, the probability of achieving protection increased to 93.8% and 97.3%, respectively, after a third dose. For measles, mumps, and rubella, the probability of achieving protection was 89.4%, 80.9%, and 94.2%, respectively. In conclusion, our findings support a more extensive vaccination schedule including three doses for diphtheria and tetanus which are in line with current international guidelines.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/petr.13599DOI Listing
February 2020

"Risk of de novo or secondary cancer after solid organ or allogeneic haematopoietic stem cell transplantation".

J Cancer Res Clin Oncol 2019 Dec 5;145(12):3125-3135. Epub 2019 Nov 5.

CHIP, Department of Infectious Diseases, Centre for Cardiac, Pulmonary and Infectious Diseases Vascular, University of Copenhagen, Rigshospitalet, Section 2100, Blegdamsvej 9, 2100 Copenhagen, Copenhagen Ø, Denmark.

Purpose: Solid organ (SOT) and allogeneic haematopoietic stem cell (HSCT) transplant recipients have elevated risks of de novo or secondary cancer. We explored risk factors hereof.

Methods: Among SOT and HSCT between January 2004 and December 2014, standardised incidence ratio (SIR) of de novo/secondary cancer compared with the Danish population was determined and risk factors were identified using Poisson regression.

Results: During a median of 3.4 (IQR 1.3-6.4) and 2.6 (0.8-5.4) person-years (PY) after SOT and HSCT, a total of 212/1656 (13%) and 75/992 (8%) persons developed cancer; SIR 3.61 (3.0-4.3) and 2.2 (1.6-3.0), resp.). SIR correlated with younger age and was highest for skin and haematological cancers for both types of transplantation. Within the cohort, cancer was associated with older age (adjusted incidence rate ratio > 50 vs ≤ 19 years, among SOT and HSCT: 9.4 (3.4-25.7) and 25.4 (5.1-126.0), resp.) and current elevated C-reactive protein (CRP) (≥ 10 vs < 10 mg/L: 2.5 (1.8-3.4) and 2.3 (1.4-3.9), resp.), but neither with prior cancer nor type of immunosuppressants.

Conclusion: Rates of de novo or secondary cancers are elevated in both SOT and HSCT compared with the general population and mainly for skin and haematological cancers. Among transplant recipients, older age and current elevated CRP are risk factors.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00432-019-03039-2DOI Listing
December 2019

Low incidence of hemorrhagic cystitis following ex vivo T-cell depleted haploidentical hematopoietic cell transplantation in children.

Bone Marrow Transplant 2020 01 16;55(1):207-214. Epub 2019 Sep 16.

Department of Pediatric Oncology and Hematology, Skåne University Hospital, Lund, Sweden.

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 TcRαβ+ (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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41409-019-0672-4DOI Listing
January 2020

Highly sensitive chimerism detection in blood is associated with increased risk of relapse after allogeneic hematopoietic cell transplantation in childhood leukemia.

Pediatr Transplant 2019 11 16;23(7):e13549. Epub 2019 Jul 16.

Department for Children and Adolescents, Pediatric Hematopoietic Stem Cell Transplantation and Immunodeficiency, Copenhagen University Hospital Rigshospitalet, Copenhagen, Denmark.

Analysis of chimerism in blood post-HCT using STR-PCR is routinely applied in parallel with quantification of MRD to predict relapse of leukemia. RQ-PCR chimerism is 10- to 100-fold more sensitive, but clinical studies in children are sparse. We analyzed IMC in blood samples following transplantation for acute lymphoblastic or myeloid leukemia in 56 children. IMC was defined as a minimum increase of (a) 0.1% or (b) 0.05% recipient DNA between two samples. The risk of relapse was higher in children with IMC of both 0.1% and 0.05% compared to children without IMC (HR 12.8 [95% CI: 3.9-41.4; P < .0001] and 7.6 [95% CI: 2.2-26.9; P < .01], respectively). The first IMC was detected at a median of 208 days prior to relapse. The 5-year cumulative incidence of relapse for children with a single IMC was 45.5% (CI 12.3-74.4) and 41.0% (14.2-66.6) for IMC above 0.1% and 0.05%, respectively. However, in 47 and 38 children never attaining IMC > 0.1% and >0.05%, 10 and 8 children relapsed, respectively. In a landmark analysis, no association was found between IMC prior to 90 days post-HCT and subsequent relapse by either classification of IMC and AUC for RQ-PCR chimerism was 54.2% (95 CI 27.7- 84.8). Although limited by a retrospective design, these results indicate that monitoring of RQ-PCR chimerism in peripheral blood may have a role in early detection of relapse in acute childhood leukemia.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/petr.13549DOI Listing
November 2019

Lung clearance index for early detection of pulmonary complications after allo-HSCT in children.

Pediatr Pulmonol 2019 07 19;54(7):1029-1038. Epub 2019 Apr 19.

Department of Pediatrics and Adolescent Medicine, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark.

Background: Pulmonary chronic graft-vs-host disease (cGvHD) after hematopoietic stem cell transplantation (HSCT) is characterized by impairment of the small airways. Assessment of lung clearance index (LCI) gained from multiple breath washout (MBW) is more sensitive than spirometry in detection of small airways disease. The aim of this study was to describe the development of LCI during the first year after pediatric HSCT and how LCI relates to other pulmonary function parameters and cGvHD.

Methods: This prospective, longitudinal study included 28 pediatric HSCT-recipients. Spirometry, Sulfur hexafluoride MBW and diffusion capacity of the lungs were performed before and at 3, 6, 9, and 12 months after HSCT. Respiratory symptoms and signs of cGvHD were recorded at each visit.

Results: Before HSCT, 47.8% had abnormal LCI and 12.5% had abnormal forced expiratory volume in 1 second (FEV ) Patients with persisting respiratory symptoms 12 months post-HSCT had higher median LCI (factor 5.7, P = 0.0018) and lower FEV z-scores (-1.5, P = 0.033) post-HSCT compared to patients free of respiratory symptoms. Overall, post-HSCT LCI values were 3.49 times higher and FEV was 2.31 z-scores lower in eight patients with cGvHD in any organ system compared with patients without cGvHD (P = 0.0089 and P < 0.0001). LCI values during the first 3 months were not predictive of pulmonary cGvHD.

Conclusion: LCI is a sensitive marker for cGvHD and high LCI values were associated with persisting respiratory symptoms after 1 year. Further evaluation of MBW in early detection of HSCT-related pulmonary complications require larger patient cohorts and closer follow-up during the first months after HSCT.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/ppul.24340DOI Listing
July 2019

Hospital admission for neurologic disorders among 5-year survivors of noncentral nervous system tumors in childhood: A cohort study within the Adult Life after Childhood Cancer in Scandinavia study.

Int J Cancer 2020 02 29;146(3):819-828. Epub 2019 Apr 29.

Childhood Cancer Research Group, Danish Cancer Society Research Center, Copenhagen, Denmark.

Large, comprehensive studies of the risk for neurologic disorders among long-term survivors of noncentral nervous system (CNS) childhood cancers are lacking. Thus, the aim of our study was to assess the lifetime risk of Nordic non-CNS childhood cancer survivors for neurologic disorders. We identified 15,967 5-year survivors of non-CNS childhood cancer diagnosed in Denmark, Iceland, Finland and Sweden in 1943-2008, and 151,118 matched population comparison subjects. In-patient discharge diagnoses of neurologic disorders were used to calculate relative risks (RRs) and absolute excess risks (AERs). A neurologic disorder was diagnosed in 755 of the survivors while 370 were expected, yielding a RR of 2.0 (95% confidence interval (CI) 1.9-2.2). The highest risks were found among survivors of neuroblastoma (4.1; 95% CI 3.2-5.3) and leukemia (2.8; 95% CI 2.4-3.2). The AER decreased from 331 (278-383) excess neurologic disorders per 100,000 person-years 5-9 years after diagnosis to 82 (46-118) ≥ 20 years after diagnosis. Epilepsy was the most common diagnosis (n = 229, 1.4% of all survivors), and significantly increased risks were seen among survivors of eight out of 12 types of childhood cancer. Survivors of neuroblastoma had remarkably high risks (RR ≥ 10) for hospitalization for paralytic syndromes and hydrocephalus, while survivors of leukemia had additional high risks for dementia and encephalopathy. In conclusion, survivors of non-CNS childhood cancer are at high risk for neurologic disorders, especially within the first decade after diagnosis. Therefore, intensive follow-up to identify those who require close management is needed.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/ijc.32341DOI Listing
February 2020

Feasibility of extracorporeal photopheresis in pediatric patients with graft-versus-host disease after hematopoietic stem cell transplantation.

Pediatr Transplant 2019 06 11;23(4):e13416. Epub 2019 Apr 11.

The Child and Adolescent Clinic, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark.

Graft-versus-host disease (GVHD) is a main cause of morbidity and mortality following hematopoietic stem cell transplantation. The cumulative incidence of acute and chronic GVHD (aGVHD, cGVHD) reaches 30%-50% and 20% in pediatric populations, respectively. Prednisolone and/or calcineurin inhibitors (CNI) are first-line treatments, but no superior second-line treatment has yet been established. Several treatments have been suggested, among others extracorporeal photopheresis (ECP). Technical advances have made treatment of pediatric patients possible; however, only few reports on the feasibility of ECP in children have been published. We retrospectively studied the feasibility, safety, and efficacy of ECP in 15 children with steroid-dependent/refractory acute or chronic GVHD, who initiated ECP treatment between April 2014 and January 2018. Only few and mild side effects directly related to the ECP procedure were registered, even in patients with low body weight. The most frequent cause of shortened or canceled ECP treatment was difficulties with vascular accesses, which were more rarely seen using central venous catheters with larger lumens and made of stiffer material. Nine patients had grade II-III aGVHD. Six of these experienced a response to ECP at day 28, while eight of nine had responded at the last ECP treatment. Six patients had cGVHD when ECP was initiated, and of these, four had a partial response at last ECP treatment. We found ECP to be a feasible and safe treatment, and particularly, children with aGVHD appeared to respond well to ECP.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/petr.13416DOI Listing
June 2019

Reduced Plasma Amino Acid Levels During Allogeneic Hematopoietic Stem Cell Transplantation Are Associated with Systemic Inflammation and Treatment-Related Complications.

Biol Blood Marrow Transplant 2019 07 22;25(7):1432-1440. Epub 2019 Mar 22.

Institute for Inflammation Research, Department of Rheumatology and Spine Disease, Rigshospitalet, Copenhagen, Denmark; Department of Pediatrics and Adolescent Medicine, Rigshospitalet, Copenhagen, Denmark.

Patients undergoing allogeneic hematopoietic stem cell transplantation (HSCT) are challenged by cytotoxic effects of the conditioning regimen, resulting in tissue damage, systemic inflammation, and increased metabolic demands for amino acids to regenerate damaged tissues, reconstitute hematopoietic cells, and establish antioxidant defenses. To date, few studies have addressed the role of plasma amino acid (PAA) levels during transplantation, and it remains unknown if amino acid deficiency can aggravate treatment-related morbidity. We determined plasma levels of the 23 human amino acids in 80 HSCT recipients (age 1.1 to 55.4 years) before conditioning and on days +7 and +21 post-transplant along with C-reactive protein (CRP) and IL-6 levels on day +7. Significant changes were observed in plasma concentrations of several human amino acids during HSCT. On day +7, numerous amino acids were inversely correlated with both CRP and IL-6, including glutamic acid, serine, alanine, glutamine, arginine, cysteine, glycine, histidine, lysine, tryptophan, threonine, taurine, proline, and methionine (r = -.22 to -.66; all P < .05). Patients who developed sinusoidal obstruction syndrome (SOS) had significantly lower mean total PAA levels compared with patients without SOS (2013 ng/L [95% confidence interval (CI), 1709 to 2318 ng/L] versus 2706 ng/L [95% CI, 2261 to 3150 ng/L]; P = .006), along with lower individual levels of glutamic acid, serine, arginine, glycine, lysine, valine, tryptophan, threonine, and proline on day +7 (all P < .05). Patients with severe acute graft-versus-host disease had a lower mean total PAA level (1922 ng/L [95% CI, 1738 to 2106 ng/L] versus 2649 ng/L [95% CI, 2244 to 3055 ng/L]; P = .014) and lower levels of serine, glutamine, cysteine, glycine, lysine, and threonine on day +7 (all P < .05). These results indicate a relationship between low concentrations of certain amino acids and the risk of treatment-related complications.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.bbmt.2019.03.018DOI Listing
July 2019

Assessment of the proposed EBMT pediatric criteria for diagnosis and severity grading of sinusoidal obstruction syndrome.

Bone Marrow Transplant 2019 09 25;54(9):1406-1418. Epub 2019 Jan 25.

Institute for Inflammation Research, Department of Rheumatology and Spine Disease, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark.

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 × 10/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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41409-018-0426-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6760545PMC
September 2019

Low burden of minimal residual disease prior to transplantation in children with very high risk acute lymphoblastic leukaemia: The NOPHO ALL2008 experience.

Br J Haematol 2019 03 24;184(6):982-993. Epub 2019 Jan 24.

Department of Paediatrics, University of Helsinki, Helsinki, Finland.

The population-based Nordic/Baltic acute lymphoblastic leukaemia (ALL) Nordic Society for Paediatric Haematology and Oncology (NOPHO) ALL2008 protocol combined minimal residual disease (MRD)-driven treatment stratification with very intense first line chemotherapy for patients with high risk ALL. Patients with MRD ≥5% at end of induction or ≥10 at end of consolidation or following two high risk blocks were eligible for haematopoietic cell transplantation (HCT) in first remission. After at least three high risk blocks a total of 71 children received HCT, of which 46 had MRD ≥5% at end of induction. Ten patients stratified to HCT were not transplanted; 12 received HCT without protocol indication. Among 69 patients with evaluable pre-HCT MRD results, 22 were MRD-positive, one with MRD ≥10 . After a median follow-up of 5·5 years, the cumulative incidence of relapse was 23·5% (95% confidence interval [CI]: 10·5-47·7) for MRD-positive versus 5·1% (95% CI: 1·3-19·2), P = 0·02) for MRD-negative patients. MRD was the only variable significantly associated with relapse (hazard ratio 9·1, 95% CI: 1·6-51·0, P = 0·012). Non-relapse mortality did not differ between the two groups, resulting in disease-free survival of 85·6% (95% CI: 75·4-97·2) and 67·4% (95% CI: 50·2-90·5), respectively. In conclusion, NOPHO block treatment efficiently reduced residual leukaemia which, combined with modern transplant procedures, provided high survival rates, also among pre-HCT MRD-positive patients.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/bjh.15761DOI Listing
March 2019

Hematopoietic stem cell transplantation for CD40 ligand deficiency: Results from an EBMT/ESID-IEWP-SCETIDE-PIDTC study.

J Allergy Clin Immunol 2019 06 17;143(6):2238-2253. Epub 2019 Jan 17.

Department of Pediatrics, University Medical Center Ulm, Ulm, Germany.

Background: CD40 ligand (CD40L) deficiency, an X-linked primary immunodeficiency, causes recurrent sinopulmonary, Pneumocystis and Cryptosporidium species infections. Long-term survival with supportive therapy is poor. Currently, the only curative treatment is hematopoietic stem cell transplantation (HSCT).

Objective: We performed an international collaborative study to improve patients' management, aiming to individualize risk factors and determine optimal HSCT characteristics.

Methods: We retrospectively collected data on 130 patients who underwent HSCT for CD40L deficiency between 1993-2015. We analyzed outcome and variables' relevance with respect to survival and cure.

Results: Overall survival (OS), event-free survival (EFS), and disease-free survival (DFS) were 78.2%, 58.1%, and 72.3% 5 years after HSCT. Results were better in transplantations performed in 2000 or later and in children less than 10 years old at the time of HSCT. Pre-existing organ damage negatively influenced outcome. Sclerosing cholangitis was the most important risk factor. After 2000, superior OS was achieved with matched donors. Use of myeloablative regimens and HSCT at 2 years or less from diagnosis associated with higher OS and DFS. EFS was best with matched sibling donors, myeloablative conditioning (MAC), and bone marrow-derived stem cells. Most rejections occurred after reduced-intensity or nonmyeloablative conditioning, which associated with poor donor cell engraftment. Mortality occurred mainly early after HSCT, predominantly from infections. Among survivors who ceased immunoglobulin replacement, T-lymphocyte chimerism was 50% or greater donor in 85.2%.

Conclusion: HSCT is curative in patients with CD40L deficiency, with improved outcome if performed before organ damage development. MAC is associated with better OS, EFS, and DFS. Prospective studies are required to compare the risks of HSCT with those of lifelong supportive therapy.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jaci.2018.12.1010DOI Listing
June 2019

Classification of death causes after transplantation (CLASS): Evaluation of methodology and initial results.

Medicine (Baltimore) 2018 Jul;97(29):e11564

Department of Infectious Diseases Centre of Excellence for Health, Immunity and Infections (CHIP) Department of Hematology Department of Cardiology, Copenhagen University Hospital/Rigshospitalet, Copenhagen Department of Nephrology, Copenhagen University Hospital/Herlev Hospital, Herlev Department of Pediatrics Department of Surgery, Copenhagen University Hospital/Rigshospitalet, Copenhagen Centre for Clinical Research, Epidemiology, Modelling and Evaluation (CREME), Institute for Global Health, University College London, London, United Kingdom Department of Hematology, Aarhus University Hospital/Skejby Hospital, Aarhus N Department of Nephrology, Copenhagen University Hospital/Rigshospitalet, Copenhagen, Denmark.

Correct classification of death causes is an important component of transplant trials.We aimed to develop and validate a system to classify causes of death in hematopoietic stem cell (HSCT) and solid organ (SOT) transplant recipients.Case record forms (CRF) of fatal cases were completed, including investigator-designated cause of death. Deaths occurring in 2010 to 2013 were used for derivation; and were validated by deaths occurring in 2013 to 2015. Underlying cause of death (referred to as recorded underlying cause) was determined through a central adjudication process involving 2 external reviewers, and subsequently compared with the Danish National Death Cause Registry.Three hundred eighty-eight recipients died 2010 to 2015 (196 [51%] SOT and 192 [49%] HSCT). The main recorded underlying causes of death among SOT and HSCT were classified as cancer (20%, 48%), graft rejection/failure/graft-versus-host-disease (35%, 28%), and infections (20%, 11%). Kappa between the investigator-designated and the recorded underlying cause of death was 0.74 (95% CI 0.69-0.80) in derivation and comparable in the validation cohort. Death causes were concordant with the Danish National Death Cause Registry in 37.2% (95% CI 31.5-42.9) and 38.4% (95% CI 28.8-48.0) in the derivation and validation cohorts, respectively.We developed and validated a method to systematically and reliably classify the underlying cause of death among transplant recipients. There was a high degree of discordance between this classification and that in the Danish National Death Cause Registry.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/MD.0000000000011564DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6086480PMC
July 2018

The value of EBV DNA in early detection of post-transplant lymphoproliferative disorders among solid organ and hematopoietic stem cell transplant recipients.

J Cancer Res Clin Oncol 2018 Aug 26;144(8):1569-1580. Epub 2018 May 26.

CHIP, Department of Infectious Diseases, Section 2100, Rigshospitalet, University of Copenhagen, Finsencentret, Blegdamsvej 9, 2100, Copenhagen Ø, Denmark.

Purpose: Emerging EBV DNAemia in plasma is considered an early sign of post-transplant lymphoproliferative disorder (PTLD). The aim of this study was to quantify the extent of benefit from screening for EBV DNAemia to detect emerging PTLD among solid organ (SOT) or hematopoietic stem cell transplant recipients (HSCT).

Methods: We used receiver operating characteristic (ROC) curves for assessing ability of models to predict PTLD. Among 2642 recipients transplanted between January 2004 and December 2014, 79 (3%) developed PTLD.

Results: EBV DNAemia was observed in 331/1784 recipients (18.6%, 95% CI 16.8-20.4) with measured EBV DNA. The area under the curve (AUC) of the ROC of EBV DNAemia to identify persons with subsequent PTLD was 72% (95% CI, 64-79%) among SOT and 59% (51-68%) among HSCT. Including clinical predictors such as age, gender, transplant year and type, high-risk EBV serostatus, and routine biochemistry in addition to EBV DNAemia increased AUC to 83% (75-90%) among SOT and 84% (79-89%) among HSCT. Among HSCT, including additional factors such as T-cell-depleting treatment, acute graft vs. host disease and donor match increased AUC to 85% (78-91%).

Conclusions: We constructed a model to better predict PTLD compared to EBV DNA screening alone which could have clinical implications.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00432-018-2674-9DOI Listing
August 2018

Donor Genotype in the Interleukin-7 Receptor α-Chain Predicts Risk of Graft-versus-Host Disease and Cytomegalovirus Infection after Allogeneic Hematopoietic Stem Cell Transplantation.

Front Immunol 2018 2;9:109. Epub 2018 Feb 2.

Institute for Inflammation Research, Department of Rheumatology and Spine Disease, Copenhagen University Hospital Rigshospitalet, Copenhagen, Denmark.

The efficacy of allogeneic hematopoietic stem cell transplantation (HSCT) is challenged by acute and chronic graft-versus-host disease (aGVHD and cGVHD) and viral infections due to long-lasting immunodeficiency. Interleukin-7 (IL-7) is a cytokine essential for T cell generation in thymus and peripheral T cell homeostasis. In this study, we investigated the impact of the single nucleotide polymorphism in the IL-7 receptor α-chain (IL-7Rα) which has previously been associated with several autoimmune diseases. We included 460 patients undergoing allogeneic HSCT after a myeloablative conditioning. Patients had a median age of 26.3 years (0.3-67.0 years), and 372 (80.9%) underwent HSCT for malignant diseases. Donors were matched sibling donors ( = 147), matched unrelated donors ( = 244) or mismatched unrelated donors ( = 69), and the stem cell source were either bone marrow ( = 329) or peripheral blood ( = 131). DNA from donors was genotyped for the IL-7Rα single nucleotide polymorphism (SNP) using an allele-specific primer extension assay (CC:  = 252, CT:  = 178, TT:  = 30). The donor T allele was associated with a higher risk of grades III-IV aGVHD (HR = 2.0, 95% CI = 1.1-3.8,  = 0.034) and with significantly increased risk of extensive cGVHD (HR = 2.0, 95% CI = 1.1-3.6,  = 0.025) after adjustment for potential risk factors. In addition, the TT genotype was associated with a higher risk of cytomegalovirus (CMV) infection post-transplant (HR = 2.4, 95% CI = 1.2-4.3,  = 0.0068). Numbers of T cells were significantly higher on day +60 in patients receiving a TT graft (CD3+: 109% increase,  = 0.0096; CD4+: 64% increase,  = 0.038; CD8+: 133% increase,  = 0.011). Donor heterozygosity for the T allele was associated with inferior overall survival (HR = 1.7, 95% CI = 1.2-2.3,  = 0.0027) and increased treatment-related mortality (HR = 2.3, 95% CI = 1.3-4.0,  = 0.0047), but was not associated with the risk of relapse ( = 0.35). In conclusion, the IL-7Rα genotype of the donor is predictive of aGVHD and cGVHD, CMV infection, and mortality following HSCT. These findings indicate that IL-7Rα SNP typing of donors may optimize donor selection and facilitate individualization of treatment in order to limit treatment-related complications.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fimmu.2018.00109DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5801419PMC
March 2019

Evaluation of infliximab as second-line treatment of acute graft versus host disease -validating response on day 7 and 28 as predictors of survival.

Bone Marrow Transplant 2018 07 1;53(7):844-851. Epub 2018 Feb 1.

Department of Hematology, National University Hospital, Rigshospitalet, Denmark.

Several immunosuppressive drugs have been proposed for second-line treatment of steroid-refractory acute graft versus host disease (aGvHD) after allogeneic hematopoietic stem cell transplantation. However, the studies on these drugs are small, retrospective, uncontrolled and use different endpoints. Therefore, it remains unknown which treatment is superior. We retrospectively evaluated 68 consecutive patients treated with infliximab for aGvHD. We adhered to recently proposed guidelines for aGvHD trials and thus evaluated response on day 7 and 28. Furthermore, we assessed the composite endpoint 6 months freedom from treatment failure (6MFTF). The majority of patients had grade III-IV aGvHD. We found that 41 patients (60%) responded on day 7 and 31 patients (46%) on day 28. Twenty-four patients (35%) achieved 6MFTF. The main reasons for failure within 6 months were death (n = 31) or additional immunosuppression (n = 16). By six and 24 months, 44 and 34% of the patients were alive respectively. Patients with response to infliximab on day 7 and 28 had significantly higher overall survival (OS) probability than non-responders. We show that response on day 7 and 28 identifies high and low risk groups. Patients who fail to respond should be identified early and offered alternative therapy.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41409-018-0099-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7086567PMC
July 2018

Reconstitution of Th17, Tc17 and Treg cells after paediatric haematopoietic stem cell transplantation: Impact of interleukin-7.

Immunobiology 2018 02 9;223(2):220-226. Epub 2017 Oct 9.

Institute for Inflammation Research, Center for Rheumatology and Spine Disease, Copenhagen University Hospital Rigshospitalet, Copenhagen, Denmark; Haematopoietic Cell Transplantation and Primary Immune Deficiency, Department of Paediatric and Adolescent Medicine, Copenhagen University Hospital Rigshospitalet, Copenhagen, Denmark.

Successful reconstitution of T lymphocytes after allogeneic haematopoietic stem cell transplantation (HSCT) is needed to establish the graft-versus-leukaemia effect and an effective anti-microbial defense, but the ratio between functionally different T-cell subsets needs to be balanced to avoid graft-versus-host disease (GVHD). IL-7 is essential for T-cell generation in the thymus and peripheral T-cell homeostasis. High IL-7 levels have been associated with impaired T-cell reconstitution, increased risk of acute GVHD and treatment-related mortality, but the underlying cellular mechanisms behind these associations have not been investigated previously. We hypothesized that increased levels of IL-7 post-transplant alters the balance between immune-regulatory T cell subsets during the post-transplant lymphocyte recovery towards a more pro-inflammatory profile. We quantified Th17 cells, Tc17 cells and Tregs in 29 children following HSCT. Th17 cell and Treg counts rose significantly from day +90 to +180 post-HSCT, and prior acute GVHD was associated with significant changes in the concentration of Tregs (9.4×10/L vs. 1.3×10/L, P=0.0052) and the Th17/Treg ratio (1.5 vs. 4.2, P=0.025). The plasma level of IL-7 at day +90 correlated inversely with Th17 cell counts (r=-0.65, P=0.0002) and the proportion of Tc17 cells (r=0.64, P=0.0005) at day +90, but not with Tregs. Furthermore, high IL-7 levels at day +7 were predictive of a less naïve T-cell phenotype at day +90. These findings add further evidence that IL-7 is a key regulatory factor that may tune the balance between functionally different T-cell subsets following HSCT.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.imbio.2017.10.023DOI Listing
February 2018

Liver diseases in Adult Life after Childhood Cancer in Scandinavia (ALiCCS): A population-based cohort study of 32,839 one-year survivors.

Int J Cancer 2018 02 7;142(4):702-708. Epub 2017 Nov 7.

Department of Paediatrics, Aarhus University Hospital, Palle Juul-Jensens Boulevard 99, Aarhus N, 8200, Denmark.

Information on late onset liver complications after childhood cancer is scarce. To ensure an appropriate follow-up of childhood cancer survivors and reducing late liver complications, the need for comprehensive and accurate information is presented. We evaluate the risk of liver diseases in a large childhood cancer survivor cohort. We included all 1-year survivors of childhood cancer treated in the five Nordic countries. A Cox proportional hazards model was used to estimate hospitalisation rate (hazard) ratios (HRs) for each liver outcome according to type of cancer. We used the risk among survivors of central nervous system tumour as internal reference. With a median follow-up time of 10 years, 659 (2%) survivors had been hospitalised at least once for a liver disease. The risk for hospitalisation for any liver disease was high after hepatic tumour (HR = 6.9) and leukaemia (HR = 1.7). The Danish sub-cohort of leukaemia treated with haematopoietic stem cell transplantation had a substantially higher risk for hospitalisation for all liver diseases combined (HR = 3.8). Viral hepatitis accounted for 286 of 659 hospitalisations corresponding to 43% of all survivors hospitalised for liver disease. The 20-year cumulative risk of viral hepatitis was 1.8% for survivors diagnosed with cancer before 1990 but only 0.3% for those diagnosed after 1990. The risk of liver disease was low but significantly increased among survivors of hepatic tumours and leukaemia. Further studies with focus on the different treatment modalities are needed to further strengthen the prevention of treatment-induced late liver complications.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/ijc.31093DOI Listing
February 2018

Estimated exposures to perfluorinated compounds in infancy predict attenuated vaccine antibody concentrations at age 5-years.

J Immunotoxicol 2017 12;14(1):188-195

e Department of Biostatistics , University of Copenhagen , Copenhagen , Denmark.

Perfluorinated alkylate substances (PFASs) are highly persistent and may cause immunotoxic effects. PFAS-associated attenuated antibody responses to childhood vaccines may be affected by PFAS exposures during infancy, where breastfeeding adds to PFAS exposures. Of 490 members of a Faroese birth cohort, 275 and 349 participated in clinical examinations and provided blood samples at ages 18 months and 5 years. PFAS concentrations were measured at birth and at the clinical examinations. Using information on duration of breastfeeding, serum-PFAS concentration profiles during infancy were estimated. As outcomes, serum concentrations of antibodies against tetanus and diphtheria vaccines were determined at age 5. Data from a previous cohort born eight years earlier were available for pooled analyses. Pre-natal exposure showed inverse associations with the antibody concentrations five years later, with decreases by up to about 20% for each two-fold higher exposure, while associations for serum concentrations at ages 18 months and 5 years were weaker. Modeling of serum-PFAS concentration showed levels for age 18 months that were similar to those measured. Concentrations estimated for ages 3 and 6 months showed the strongest inverse associations with antibody concentrations at age 5 years, particularly for tetanus. Joint analyses showed statistically significant decreases in tetanus antibody concentrations by 19-29% at age 5 for each doubling of the PFAS exposure in early infancy. These findings support the notion that the developing adaptive immune system is particularly vulnerable to immunotoxicity during infancy. This vulnerability appears to be the greatest during the first 6 months after birth, where PFAS exposures are affected by breast-feeding.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1080/1547691X.2017.1360968DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6190594PMC
December 2017

Serum Vaccine Antibody Concentrations in Adolescents Exposed to Perfluorinated Compounds.

Environ Health Perspect 2017 07 26;125(7):077018. Epub 2017 Jul 26.

Department of Biostatistics, University of Copenhagen, Copenhagen, Denmark

Background: Postnatal exposure to perfluorinated alkylate substances (PFASs) is associated with lower serum concentrations of specific antibodies against certain childhood vaccines at 7 y.

Objectives: We prospectively followed a Faroese birth cohort to determine these associations at 13 y.

Methods: In 516 subjects (79% of eligible cohort members) who were 13 years old, serum concentrations of PFASs and of antibodies against diphtheria and tetanus were measured and were compared with data from the previous examination at 7 y. Multiple regression analyses and structural equation models were applied to determine the association between postnatal PFAS exposures and antibody concentrations.

Results: Serum concentrations of PFASs and antibodies generally declined from 7 y to 13 y. However, 68 subjects had visited the emergency room and had likely received a vaccination booster, and a total of 202 children showed higher vaccine antibody concentrations at 13 y than at 7 y. Therefore, separate analyses were conducted after exclusion of these two subgroups. Diphtheria antibody concentrations decreased at elevated PFAS concentrations at 13 y and 7 y; the associations were statistically significant for perfluorodecanoate (PFDA) at 7 y and for perfluorooctanoate (PFOA) at 13 y, both suggesting a decrease by ∼25% for each doubling of exposure. Structural equation models showed that a doubling in PFAS exposure at 7 y was associated with losses in diphtheria antibody concentrations at 13 y of 10–30% for the five PFASs. Few associations were observed for anti-tetanus concentrations.

Conclusions: These results are in accord with previous findings of PFAS immunotoxicity at current exposure levels. https://doi.org/10.1289/EHP275.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1289/EHP275DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5744724PMC
July 2017
-->