Incidence of Refeeding Syndrome in Critically Ill Children With Nutritional Support.

Introduction: Early enteral nutrition is recommended for critically ill children, potentially exposing those who are undernourished to the risk of refeeding syndrome. However, data on its incidence is lacking, and the heterogeneity of diagnostic criteria and frequent electrolyte disorders in this population make its diagnosis complex. In 2020, the American Society for Parenteral and Enteral Nutrition (ASPEN) developed consensus recommendations for identifying patients at risk and with refeeding syndrome. These state that undernourished children are considered at risk of refeeding syndrome; those who develop one significant electrolyte disorder (decrease ≥ 10% in phosphorus, potassium, and/or magnesium) within the first five days of nutritional support, combined with a significant increase in energy intake, are considered to have refeeding syndrome. The aim of this study was to determine the incidence of refeeding syndrome according to the ASPEN definition in critically ill children on nutritional support. Materials and Methods: A secondary analysis of two prospective cohorts conducted in a tertiary pediatric intensive care unit in France was undertaken, and additional data were retrospectively collected. Children included were those (0-18 years) admitted to the pediatric intensive care unit with a minimum of one phosphorus, potassium, and/or magnesium assay and who received exclusive or supplemental nutritional support. Undernourished children (body mass index z-score < -2 standard deviations) were considered at risk of refeeding syndrome. The ASPEN critiera were used to identify those with probable refeeding syndrome. Results: A total of 1,261 children were included in the study, with 199 children (15.8%) classified as undernourished, who were at risk of refeeding syndrome. Of these, 93 children were identified as having probable refeeding syndrome, giving an overall incidence of 7.4%. The incidence rate among at-risk children was 46.7%. Most patients (58.1%) were classified as having severe refeeding syndrome. Conclusion: Refeeding syndrome remains difficult to diagnose in critically ill children, due to frequent confounding factors impacting electrolyte plasma levels. These findings suggest that refeeding syndrome incidence may be high in undernourished children, and that refeeding syndromes can be severe. Further prospective studies using the ASPEN definition and risk criteria are required.

Haematopoietic Stem Cell Transplantation Results in Extensive Remodelling of the Clonal T Cell Repertoire in Multiple Sclerosis.

Autologous haematopoietic stem cell transplantation (AHSCT) is a vital therapeutic option for patients with highly active multiple sclerosis (MS). Rates of remission suggest AHSCT is the most effective form of immunotherapy in controlling the disease. Despite an evolving understanding of the biology of immune reconstitution following AHSCT, the mechanism by which AHSCT enables sustained disease remission beyond the period of lymphopenia remains to be elucidated. Auto-reactive T cells are considered central to MS pathogenesis. Here, we analyse T cell reconstitution for 36 months following AHSCT in a cohort of highly active MS patients. Through longitudinal analysis of sorted naïve and memory T cell clones, we establish that AHSCT induces profound changes in the dominant T cell landscape of both CD4+ and CD8+ memory T cell clones. Lymphopenia induced homeostatic proliferation is followed by clonal attrition; with only 19% of dominant CD4 (p <0.025) and 13% of dominant CD8 (p <0.005) clones from the pre-transplant repertoire detected at 36 months. Recovery of a thymically-derived CD4 naïve T cell repertoire occurs at 12 months and is ongoing at 36 months, however diversity of the naïve populations is not increased from baseline suggesting the principal mechanism of durable remission from MS after AHSCT relates to depletion of putative auto-reactive clones. In a cohort of MS patients expressing the MS risk allele HLA DRB1*15:01, public clones are probed as potential biomarkers of disease. AHSCT appears to induce sustained periods of disease remission with dynamic changes in the clonal T cell repertoire out to 36 months post-transplant.

Sustained immunotolerance in multiple sclerosis after stem cell transplant.

OBJECTIVE: Autologous haematopoietic stem cell transplantation (AHSCT) has the potential to induce sustained periods of disease remission in multiple sclerosis (MS), which is an inflammatory disease of the central nervous system (CNS) characterised by demyelination and axonal degeneration. However, the mechanisms associated with durable treatment responses in MS require further elucidation. METHODS: To characterise the longer term immune reconstitution effects of AHSCT at 24 and 36 months (M) post-transplant, high-dimensional immunophenotyping of peripheral blood mononuclear cells from 22 MS patients was performed using two custom-designed 18-colour flow cytometry panels. RESULTS: The higher baseline frequencies of specific pro-inflammatory immune cells (T-helper-17 (Th17) cells, mucosal-associated invariant T-cells and CNS-homing T-conventional (T-conv) cells observed in MS patients were decreased post-AHSCT by 36M. This was accompanied by a post-AHSCT increase in frequencies and absolute counts of immunoregulatory CD56hi natural killer cells at 24M and terminally differentiated CD8+ CD28- CD57+ cells until 36M. A sustained increase in the proportion of naïve B-cells, with persistent depletion of memory B-cells and plasmablasts was observed until 36M. Reconstitution of the B-cell repertoire was accompanied by a reduction in the frequency of circulating T-follicular helper cells (cTfh) expressing programmed cell death-1 (PD1+ ) at 36M. Associations between frequency dynamics and clinical outcomes indicated only responder patients to exhibit a decrease in Th17, CNS-homing T-conv and PD1+ cTfh pro-inflammatory subsets at 36M, and an increase in CD39+ T-regulatory cells at 24M. INTERPRETATION: AHSCT induces substantial recalibration of pro-inflammatory and immunoregulatory components of the immune system of MS patients for up to 36M post-transplant.

Altered Immune Reconstitution in Allogeneic Stem Cell Transplant Recipients With Human Immunodeficiency Virus (HIV).

BACKGROUND: Persons living with human immunodeficiency virus (HIV) are at elevated risk of developing the malignant diseases that require allogeneic stem cell transplantation (ASCT). Recent data suggest that these individuals are also at an elevated risk of certain complications post-ASCT. This risk may result from preexisting HIV-related factors affecting dynamics of immune reconstitution post-ASCT. However, to date, there has been little work describing the dynamics of immune reconstitution post-ASCT in persons with HIV and none comparing these data to controls without HIV. METHODS: We assessed T-cell reconstitution in 6 ASCT with HIV recipients (HIV+ASCT) compared to a control population of 21 ASCT without HIV recipients. In a subset of HIV+ASCT recipients we performed additional flow cytometry profiling of CD8+ T-cell subsets and antigen specificity of reconstituting CD4+ and CD8+ T cells. RESULTS: We observe no difference in post-ASCT CD4+ T cells between HIV+ASCT and HIV-negative ASCT recipients, despite much lower pre-ASCT CD4+ T-cell counts in the HIV+ASCT group. In contrast, we observed significantly higher CD8+ T-cell numbers in the HIV+ASCT group post-ASCT. The reconstituting CD8+ T-cells were predominantly CD45RO+, whereas homing markers and antigen specificity of these cells varied between participants. CONCLUSION: This study represents the most extensive characterization of immune-reconstitution post-ASCT in persons with HIV, and the first to our knowledge to compare these data to ASCT controls without HIV. The results indicate that immune reconstitution in this group can be affected by preexisting HIV infection and post-ASCT antigen exposure.

Prospective phase II clinical trial of autologous haematopoietic stem cell transplant for treatment refractory multiple sclerosis.

BACKGROUND: Autologous haematopoietic stem cell transplantation (AHSCT) has been explored as a therapeutic intervention in multiple sclerosis (MS) over the last two decades; however, prospective clinical trials of the most common myeloablative conditioning regimen, BEAM, are limited. Furthermore, patient selection, optimal chemotherapeutic regimen and immunological changes associated with disease response require ongoing exploration. We present the outcomes, safety and immune reconstitution (IR) of patients with active, treatment refractory MS. METHODS: This study was a single-centre, phase II clinical trial of AHSCT for patients with active relapsing remitting (RRMS) and secondary progressive MS (SPMS). Patients underwent AHSCT using BEAM (carmustine, etoposide, cytarabine, melphalan)+antithymocyte globulin chemotherapeutic regimen. OUTCOMES: The primary outcome was event-free survival (EFS); defined as no clinical or radiological relapses and no disability progression. Multiparameter flow cytometry was performed for evaluation of post-transplant IR in both MS and lymphoma patients receiving the same chemotherapy regimen. RESULTS: Thirty-five patients (20 RRMS, 15 SPMS) completed AHSCT, with a median follow-up of 36 months (range 12-66). The median Expanded Disability Status Scores (EDSS) was 6 (2-7) and patients had failed a median of 4 (2-7) disease modifying therapies. 66% failed treatment with natalizumab. EFS at 3 years was 60%, (70% RRMS). Sustained improvement in EDSS was seen in 15 (44%) of patients. There was no treatment-related mortality. A sustained rise in CD39+ T regulatory cells, immunosuppressive CD56hi natural killer cells and ablation of proinflammatory mucosal-associated invariant T cells was seen for 12 months following AHSCT in patients with MS. These changes did not occur in patients with lymphoma receiving the same chemotherapy for AHSCT. CONCLUSIONS: The EFS in our MS cohort is significantly greater than other high-efficacy immunosuppressive therapies and similar to other AHSCT studies despite a more heavily pretreated cohort. TRIAL REGISTRATION NUMBER: ACTRN12613000339752.