Wiskott-Aldrich syndrome (WAS) is a multifaceted monogenic disorder with a broad disease spectrum and variable disease severity and a variety of treatment options including allogeneic hematopoietic stem cell transplantation (HSCT) and gene therapy (GT). No reliable biomarker exists to predict disease course and outcome for individual patients. A total of 577 patients with a WAS variant from 26 countries and a median follow-up of 8.9 years (range, 0.3-71.1), totaling 6118 patient-years, were included in this international retrospective study. Overall survival (OS) of the cohort (censored at HSCT or GT) was 82% (95% confidence interval, 78-87) at age 15 years and 70% (61-80) at 30 years. The type of variant was predictive of outcome: patients with a missense variant in exons 1 or 2 or with the intronic hot spot variant c.559+5G>A (class I variants) had a 15-year OS of 93% (89-98) and a 30-year OS of 91% (86-97), compared with 71% (62-81) and 48% (34-68) in patients with any other variant (class II; P < .0001). The cumulative incidence rates of disease-related complications such as severe bleeding (P = .007), life-threatening infection (P < .0001), and autoimmunity (P = .004) occurred significantly later in patients with a class I variant. The cumulative incidence of malignancy (P = .6) was not different between classes I and II. It confirms the spectrum of disease severity and quantifies the risk for specific disease-related complications. The class of the variant is a biomarker to predict the outcome for patients with WAS.

Introduction: Per- and polyfluoroalkyl substances (PFASs) have immunotoxic effects in children while studies in adults, including recent studies on the SARS-CoV-2 vaccine response have been less consistent. In a cohort of 50-69-year-olds repeatedly vaccinated against COVID-19 in Denmark from early 2021, we aimed to assess the association between serum-PFAS concentrations and SARS-CoV-2 antibody responses. Methods: We assessed serum-PFAS concentrations among 371 middle-aged adults from the National Cohort Study of Effectiveness and Safety of SARS-CoV-2 vaccines (ENFORCE) who had received their first vaccination against COVID-19. Following the second dose and the booster (third) Pfizer-BioNTech mRNA vaccination, we measured the specific spike IgG antibody response. Associations between serum-PFAS concentrations at inclusion and spike IgG antibody concentrations after vaccination were assessed using median regression, and analyses were adjusted for age, sex, presence of diabetes, number of vaccines received, and time since vaccination. We further examined the associations between serum-PFAS concentrations at inclusion and changes in spike IgG antibody concentration between the second dose and booster (third) vaccination. Results: Serum-PFAS concentrations were not associated with spike IgG antibody concentrations after the SARSCoV-2 vaccinations, but the increase in response after the booster (third) vaccination compared to after the second vaccination was consistently lower at higher serum-PFAS concentrations. Each doubling in the concentration of seven serum-PFASs was associated with a 802 BAU/mL lower median increase in spike IgG antibody response after the booster (third) vaccination (95% CI: -1812; 208) adjusted for confounders. Discussion: As many adults were probably not immunological na & iuml;ve prior to vaccination, our results were likely affected by individual variability in immune response to the vaccination. Despite this uncertainty, the diminished increase in SARS-CoV-2 spike antibody response after the booster (third) vaccination at higher PFAS exposure may potentially reflect an immunotoxic impact of the PFASs.

Analysis of chimerism in blood post‐HCT using STR‐PCR is routinely applied in parallel with quantification of MRD to predict relapse of leukemia. Real time quantitative PCR (RQ-PCR) chimerism is 10‐ to 100‐fold more sensitive, but clinical studies in children are sparse. In a prospective multicenter study, we analyzed increasing mixed chimerism (IMC) in blood samples following transplantation for leukemia in 64 children. IMC was defined as a minimum increase of either 0.1% or 0.05% recipient DNA between two samples or a ≥10-fold increase. Samples closer than 30 days to diagnosis of relapse were omitted. The risk of relapse was higher in children with IMC of both 0.1% and 0.05% compared to children without IMC (27.8 (95% CI 4.4-175.8; P<.001), and 18.4 (95% CI 2.8-120.5; P=0.002), respectively). From the date of IMC, the 3-year CI of relapse or MRD-positivity was 26.7% (CI 9.4-47.0) and 18.5% (6.4-35.3) for IMC ≥ 0.1% (n=27) and ≥ 0.05% (n= 40), respectively. In the subset of children without an IMC ≥ 0.1% or ≥ 0.05%, CI of relapse or molecular relapse were 16.7% (5.0 -34.1) and 10.8% (3.4 -23.3), respectively. In all cases with a relapse undetectable by IMC, MRD remained undetectable prior to relapse and standard chimerism negative. In a landmark analysis, neither an IMC ≥ 0.1% nor ≥ 0.05% prior to 90 days post‐HCT was significantly associated with an increased relapse incidence. These results indicate that the serial monitoring of RQ‐PCR chimerism in peripheral blood post-HCT may be a valuable supplement to the minimal residual disease analysis for an early detection of relapse in acute childhood leukemia.

Scandinavian Journal of ImmunologyVolume 97, Issue 3 e13243 LETTER TO THE EDITOR A novel DOCK2 variant in siblings with severe combined immunodeficiency Maria Anna Bruusgaard-Mouritsen, Corresponding Author Maria Anna Bruusgaard-Mouritsen [email protected] orcid.org/0000-0003-4259-5711 Section for Diagnostic Immunology, Department of Clinical Immunology, Copenhagen University Hospital – Rigshospitalet, Copenhagen, Denmark Correspondence Maria Anna Bruusgaard-Mouritsen, Section for Diagnostic Immunology 7631, Department of Clinical Immunology, Copenhagen University Hospital – Rigshospitalet, Ole Maaløes Vej 26, 2200 Copenhagen N, Denmark. Email: [email protected]Search for more papers by this authorTania Masmas, Tania Masmas Department of Paediatrics and Adolescent Medicine, Paediatric Haematopoietic Stem Cell Transplantation and Immunodeficiency, Copenhagen University Hospital – Rigshospitalet, Copenhagen, DenmarkSearch for more papers by this authorLine Borgwardt, Line Borgwardt Center for Genomic Medicine, Copenhagen University Hospital – Rigshospitalet, Copenhagen, DenmarkSearch for more papers by this authorLusine Nazaryan-Petersen, Lusine Nazaryan-Petersen Center for Genomic Medicine, Copenhagen University Hospital – Rigshospitalet, Copenhagen, DenmarkSearch for more papers by this authorCarsten Heilmann, Carsten Heilmann Department of Paediatrics and Adolescent Medicine, Paediatric Haematopoietic Stem Cell Transplantation and Immunodeficiency, Copenhagen University Hospital – Rigshospitalet, Copenhagen, DenmarkSearch for more papers by this authorHans O. Madsen, Hans O. Madsen Section for Diagnostic Immunology, Department of Clinical Immunology, Copenhagen University Hospital – Rigshospitalet, Copenhagen, DenmarkSearch for more papers by this authorHanne Vibeke Marquart, Hanne Vibeke Marquart Section for Diagnostic Immunology, Department of Clinical Immunology, Copenhagen University Hospital – Rigshospitalet, Copenhagen, DenmarkSearch for more papers by this author Maria Anna Bruusgaard-Mouritsen, Corresponding Author Maria Anna Bruusgaard-Mouritsen [email protected] orcid.org/0000-0003-4259-5711 Section for Diagnostic Immunology, Department of Clinical Immunology, Copenhagen University Hospital – Rigshospitalet, Copenhagen, Denmark Correspondence Maria Anna Bruusgaard-Mouritsen, Section for Diagnostic Immunology 7631, Department of Clinical Immunology, Copenhagen University Hospital – Rigshospitalet, Ole Maaløes Vej 26, 2200 Copenhagen N, Denmark. Email: [email protected]Search for more papers by this authorTania Masmas, Tania Masmas Department of Paediatrics and Adolescent Medicine, Paediatric Haematopoietic Stem Cell Transplantation and Immunodeficiency, Copenhagen University Hospital – Rigshospitalet, Copenhagen, DenmarkSearch for more papers by this authorLine Borgwardt, Line Borgwardt Center for Genomic Medicine, Copenhagen University Hospital – Rigshospitalet, Copenhagen, DenmarkSearch for more papers by this authorLusine Nazaryan-Petersen, Lusine Nazaryan-Petersen Center for Genomic Medicine, Copenhagen University Hospital – Rigshospitalet, Copenhagen, DenmarkSearch for more papers by this authorCarsten Heilmann, Carsten Heilmann Department of Paediatrics and Adolescent Medicine, Paediatric Haematopoietic Stem Cell Transplantation and Immunodeficiency, Copenhagen University Hospital – Rigshospitalet, Copenhagen, DenmarkSearch for more papers by this authorHans O. Madsen, Hans O. Madsen Section for Diagnostic Immunology, Department of Clinical Immunology, Copenhagen University Hospital – Rigshospitalet, Copenhagen, DenmarkSearch for more papers by this authorHanne Vibeke Marquart, Hanne Vibeke Marquart Section for Diagnostic Immunology, Department of Clinical Immunology, Copenhagen University Hospital – Rigshospitalet, Copenhagen, DenmarkSearch for more papers by this author First published: 21 December 2022 https://doi.org/10.1111/sji.13243Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL REFERENCES 1Chen Y, Meng F, Wang B, He L, Liu Y, Liu Z. Dock2 in the development of inflammation and cancer. Eur J Immunol. 2018; 48(6): 915- 922. 2Moens L, Gouwy M, Bosch B, et al. Human DOCK2 deficiency: report of a novel mutation and evidence for neutrophil dysfunction. J Clin Immunol. 2019; 39(3): 298- 308. 3Aytekin ES, Çağdaş D, Tan Ç, Çavdarlı B, Bilgiç I, Tezcan İ. Hematopoietic stem cell transplantation complicated with EBV associated hemophagocytic lymphohistiocytosis in a patient with DOCK2 deficiency. Turk J Pediatr. 2021; 63(6): 1072- 1077. 4Bækvad-Hansen M, Adamsen D, Bybjerg-Grauholm J, Hougaard DM. Implementation of SCID screening in Denmark. Int J Neonatal Screen. 2021; 7(3): 54. 5Dobbs K, Domínguez Conde C, Zhang SY, et al. Inherited DOCK2 deficiency in patients with early-onset invasive infections. N Engl J Med. 2015; 372(25): 2409- 2422. 6Sharifinejad N, Sadri H, Kalantari A, et al. First patient in the Iranian Registry with novel DOCK2 gene mutation, presenting with skeletal tuberculosis, and review of literature. Allergy Asthma Clin Immunol. 2021; 17(1): 126. 7Richards S, Aziz N, Bale S, et al. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med. 2015; 17(5): 405- 424. 8Alosaimi MF, Shendi H, Beano A, et al. T-cell mitochondrial dysfunction and lymphopenia in DOCK2-deficient patients. J Allergy Clin Immunol. 2019; 144(1): 306- 309.e2. 9D'Astous-Gauthier K, Desjardins A, Marois L. DOCK2 deficiency diagnosed 18 years after hematopoietic stem cell transplantation. J Clin Immunol. 2021; 41(6): 1400- 1402. 10Haddad E, Leroy S, Buckley RH. B-cell reconstitution for SCID: should a conditioning regimen be used in SCID treatment? J Allergy Clin Immunol. 2013; 131(4): 994- 1000. Volume97, Issue3March 2023e13243 ReferencesRelatedInformation

The effect of higher FOXP3 mRNA expression by recipient pre‐transplant CD4+ T cells on leukaemia relapse was analysed in a series of 106 patients who received allogeneic haematopoietic stem cell transplantation after myeloablative conditioning with or without antithymocyte globulin (ATG) due to acute leukaemia in 1st or 2nd complete remission. FOXP3 mRNA was measured by qPCR in purified CD4+ T cells from blood obtained before conditioning. Higher FOXP3 mRNA expression was associated with an increased relapse risk when conditioning included ATG ( n = 43, hazard ratio [HR] 11.0 [2.50–48.4], p = 0.00001). No effect was observed in patients not receiving ATG (HR 0.95 [0.53–1.81]).

Background and aim: Perfluoroalkyl substances (PFAS) have been in production for more than half a century and is still used in numerous consumer products. Humans are exposed to PFAS through contaminated food and water as well as dust from treated materials. These chemicals bioaccumulate and are widespread in the environment, and populations relying on a marine diet are thus often more exposed. The aim of this study was to examine the association between Greenlandic children's exposure to major environmental chemicals and their concentrations of diphtheria and tetanus vaccine antibodies after vaccination. Methods: The study is based on cross-sectional data from Greenlandic children aged 7–12 years examined during 2012–2015. Among 175 children with known vaccination records, 169 provided a serum sample with sufficient volume to measure PFAS and specific antibodies against diphtheria and tetanus. Associations were examined in linear and logistic regression models. Results: We found higher serum-PFAS concentrations to be associated with lower diphtheria antibody concentrations after vaccination and with increased odds of having diphtheria antibody concentrations below the protective level. For each 1 ng/mL increase in serum concentrations of perfluorohexane sulfonic acid (PFHxS), perfluorooctane sulfonic acid (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. Conclusions: Our findings emphasize the risk of immunotoxicity associated with PFAS exposure also in this Arctic population. Keywords: PFAS, Children, Vaccine antibodies, Immunotoxicity, Greenland

Type I interferons (IFN-I) play a critical role in human antiviral immunity, as demonstrated by the exceptionally rare deleterious variants of IFNAR1 or IFNAR2. We investigated five children from Greenland, Canada, and Alaska presenting with viral diseases, including life-threatening COVID-19 or influenza, in addition to meningoencephalitis and/or hemophagocytic lymphohistiocytosis following live-attenuated viral vaccination. The affected individuals bore the same homozygous IFNAR2 c.157T>C, p.Ser53Pro missense variant. Although absent from reference databases, p.Ser53Pro occurred with a minor allele frequency of 0.034 in their Inuit ancestry. The serine to proline substitution prevented cell surface expression of IFNAR2 protein, small amounts of which persisted intracellularly in an aberrantly glycosylated state. Cells exclusively expressing the p.Ser53Pro variant lacked responses to recombinant IFN-I and displayed heightened vulnerability to multiple viruses in vitro-a phenotype rescued by wild-type IFNAR2 complementation. This novel form of autosomal recessive IFNAR2 deficiency reinforces the essential role of IFN-I in viral immunity. Further studies are warranted to assess the need for population screening.

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.

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 (p < 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 (p = 0.0004 and p = 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.

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.

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.

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.

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.

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.

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 (IGF1), rs978458 (IGF1), or rs2854744 (IGFBP3) serum levels remained normal during the whole period. In accordance, maximum C-reactive protein levels were lower for these genotypes of IGF1 (rs1520220: median 66 vs. 102 mg/L, P = 0.005 and rs978458: 53 vs. 104 mg/L, P < 0.001), translating into borderline significant superior survival (P = 0.060 for rs1520220) and reduced treatment-related mortality (P = 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.

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 as well.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 ordinal and 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 odds ratio (OR) of 2.19 (95% confidence interval, CI, 1.39-3.46) for increasing severities of the disease, although the OR decreased to 1.77 (95% CI, 1.09, 2.87) after adjustment for age, sex, sampling site and interval between blood sampling and diagnosis.Conclusions:Measures of individual exposures to immunotoxic PFASs included PFBA that accumulates in the lungs. Elevated plasma-PFBA concentrations were associated with an increased risk of more severe course of CIVID-19. Given the low background exposure levels in this study, the role of PFAS exposure in COVID-19 needs to be ascertained in populations with elevated exposures.

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.

Background: Immunotoxicity has been selected as the critical effect of early-life exposures to perfluorinated alkylate substances (PFASs) in a 2020 draft opinion by the European Food Safety Authority. However, uncertainty prevails in regard to the most vulnerable age at exposure.Methods: A birth cohort of 490 children was recruited in the Faroe Islands in 2007-2009 and followed up with blood samples at ages 18 months, 5 and 9 years. PFAS concentrations were quantified in umbilical cord blood collected at birth and at postnatal examinations. Diphtheria and tetanus IgG antibody concentrations were quantified at ages 5 and 9 using ELISA assays. As blood samples from infancy were not available, we modeled serum-PFAS concentrations at ages 3 and 6 months using structural equations. We used linear regressions to examine PFAS associations with age-9 antibody concentrations allowing for sex-specific associations.Results: PFAS exposures were lower than in a previous Faroese birth cohort. In cross-sectional analyses at age 9, PFAS concentrations did not show any associations with tetanus or diphtheria antibodies. However, a doubling in the cord blood concentration of perfluorooctanoic acid (PFOA) was associated with a decrease in tetanus (12.6%; 95%CI: -22.1, -1.9) and diphtheria (16.3%; 95% CI: -28.2, -2.3) antibody concentrations. Tendencies were less clear at other ages and for other PFASs. A doubling of the modeled PFOA concentration at 3 months was associated with lower tetanus antibodies (20.8%; 95% CI: -35.0, -3.5%) at age 9. Weaker associations were observed for exposures at age 6 months. There was some indication of sex-specific associations that varied by antibody type.Conclusions; Early-life exposure to PFOA has the strongest impact on vaccine antibody concentrations in later childhood.