scholarly journals GPR Expression in Intestinal Biopsies From SCT Patients Is Upregulated in GvHD and Is Suppressed by Broad-Spectrum Antibiotics

2021 ◽  
Vol 12 ◽  
Author(s):  
Sakhila Ghimire ◽  
Daniela Weber ◽  
Katrin Hippe ◽  
Elisabeth Meedt ◽  
Matthias Hoepting ◽  
...  
Keyword(s):  
Broad Spectrum ◽  
Foxp3 Expression ◽  
Short Chain Fatty Acids ◽  
Experimental Models ◽  
Foxp3 Mrna ◽  
Hematopoietic Stem ◽  
Graft Versus Host ◽  
Broad Spectrum Antibiotics ◽  
G Protein Coupled ◽  
Nlrp3 Expression

Microbiota can exert immunomodulatory effects by short-chain fatty acids (SCFA) in experimental models of graft-versus-host disease (GvHD) after allogeneic hematopoietic stem cell transplantation (allo-SCT). Therefore we aimed to analyze the expression of SCFAs sensing G-protein coupled receptor GPR109A and GPR43 by quantitative PCR in 338 gastrointestinal (GI) biopsies obtained from 199 adult patients undergoing allo-SCT and assessed the interaction of GPR with FOXP3 expression and regulatory T cell infiltrates. GPR expression was strongly upregulated in patients with stage II-IV GvHD (p=0.000 for GPR109A, p=0.01 for GPR43) and at the onset of GvHD (p 0.000 for GPR109A, p=0.006 for GPR43) and correlated strongly with FOXP3 and NLRP3 expression. The use of broad-spectrum antibiotics (Abx) drastically suppressed GPR expression as well as FOXP3 expression in patients’ gut biopsies (p=0.000 for GPRs, FOXP3 mRNA and FOXP3+ cellular infiltrates). Logistic regression analysis revealed treatment with Abx as an independent factor associated with GPR and FOXP3 loss. The upregulation of GPRs was evident only in the absence of Abx (p=0.001 for GPR109A, p=0.014 for GPR43) at GvHD onset. Thus, GPR expression seems to be upregulated in the presence of commensal bacteria and associates with infiltration of FOXP3+ T regs, suggesting a protective, regenerative immunomodulatory response. However, Abx, which has been shown to induce dysbiosis, interferes with this protective response.

Rate of positive blood cultures after 3 days of empiric antibiotics in pediatric cancer

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 9535-9535
Author(s):  
B. Kanathezhath ◽  
J. Feusner
Keyword(s):  
Blood Culture ◽  
Pediatric Oncology ◽  
Broad Spectrum ◽  
Signs And Symptoms ◽  
Blood Cultures ◽  
Coagulase Negative Staphylococcus ◽  
Cell Transplant ◽  
Hematopoietic Stem ◽  
Broad Spectrum Antibiotics ◽  
Related Mortality

9535 Background: Infections continue to be a major cause of morbidity and mortality in pediatric oncology patients (pts) with febrile neutropenia (FN). The proportion of such pts who have bacteremia documented after 72 hours (hrs) of broad-spectrum antibiotics, in the absence of local or systemic signs of infection, has not been previously reported. Methods: We conducted a retrospective analysis of all FN oncology pts admitted to our hospital during the period of August 1999 to October 2006. Blood cultures (BCs) from pts who were persistently febrile more than 3 days after initiation of empiric broad-spectrum antibiotics (ceftazidime and tobramycin) were analyzed. Medical records of pts with positive late blood cultures (LBCs) after 72 hrs were reviewed for onset of new signs and symptoms of infection. Hematopoietic stem cell transplant and HIV pts were excluded. Results: Ninety-seven episodes of persistent fever occurred in 71 FN pts. The total number of positive BCs in the first 72 hours was 24 (33.8%). Three (4.2%) of the persistently febrile pts had positive LBC. Of these 3 pts, one had preceding new signs and symptoms. Another had a probable contaminant (only 1 positive BC for coagulase-negative staphylococcus). Only one pt (1.4%) had positive LBC without any new local or systemic signs of infection. The observed frequency of positive LBC was 4.2% for pts and 0.8% (3/391) for total cultures obtained after 72 hours. There were no changes made in the antibiotic regimen of pts with positive LBC and none of them suffered from sepsis related mortality. Conclusions: This is the first report of late blood culture results in FN pediatric oncology pts. The practice of obtaining daily blood culture in such pts who are stable after 72 hrs of broad- spectrum antibiotics has a low yield (<5%), and even lower (<2%) if pts with new signs or symptoms at the LBC are excluded. This observation, if confirmed by larger studies from other centers, could lead to a more efficient, risk based strategy for following these pts. No significant financial relationships to disclose.

scholarly journals 2666. De-escalation of Broad-Spectrum Antibiotics in Hematopoietic Stem Cell Transplant Patients During Initial Episode of Febrile Neutropenia

2019 ◽  
Vol 6 (Supplement_2) ◽  
pp. S934-S934
Author(s):  
Lindsey Rearigh ◽  
Erica J Stohs ◽  
Alison Freifeld ◽  
Andrea Zimmer
Keyword(s):  
Stem Cell ◽  
Febrile Neutropenia ◽  
Hematopoietic Stem Cell ◽  
Broad Spectrum ◽  
Hematopoietic Stem Cell Transplant ◽  
Stem Cell Transplant ◽  
Cell Transplant ◽  
Hematopoietic Stem ◽  
Broad Spectrum Antibiotics ◽  
Significant Difference

Abstract Background Febrile neutropenia (FN) is a common and serious complication in patients undergoing hematopoietic stem cell transplant (HSCT). Typically, broad-spectrum antibiotics (BSA) are promptly initiated with controversy on timing of de-escalation. ECIL 2013 guidelines suggest de-escalation after 72 hours if the patient is infection free and afebrile for at least 48 hours. Conversely, the 2011 IDSA recommends continuing BSA in patients who defervesce until absolute neutrophil count (ANC) recovery. In 2014, our center’s practice changed to early de-escalation and we sought to compare outcomes between the two practices. Methods We retrospectively analyzed patients who underwent a HSCT in 2013 and 2017 with an episode of FN and negative infectious work up. The standard care group (SCG) were continued on BSA until ANC recovery. The early de-escalation group (EDG) de-escalated to fluoroquinolone prophylaxis at least 24 hours prior to ANC recovery after the patient was fever free for 48 hours. The primary end-point was duration of BSA. Secondary endpoints included 30-day mortality, re-hospitalization and length of stay (LOS) from FN. Median values were compared with the Mann–Whitney test. Results Among 229 HSCT patients, 155 (68%) developed FN post-transplant and of those 97 (63%) were without infection (13 EDG and 84 SCG). Initial FN duration of BSA was less in the EDG (3.09 days vs. 4.69 days, P = 0.069). Total antibiotic free days to 30 day follow-up were similar (EDG 24.08 vs SCG 25.19, P = 0.81). Duration of neutropenia was less in the SCG with 7.99 days compared with 11.69 days in the EDG (P = 0.007), but duration of initial fever was less in the EDG (2.55 days vs. 3.33 days, P = 0.023). 30 day mortality was 0% in both groups. Rates of re-hospitalization within 30 days were approximately the same (7.1% vs. 7.6%). LOS from FN was not significantly different with 6.68 days in SCG and 7.75 days in EDG (P = 0.140). More new bacterial infections were identified within 30 days of FN in the SCG than the EDG (10.7% vs. 7.6%). Conclusion Early BSA de-escalation resulted in no significant difference in LOS from FN and fewer days of BSA with 30-day mortality and re-hospitalization rates similar. This data suggest de-escalating BSA prior to ANC recovery is likely safe and leads to less BSA exposure, but more multi-center data are needed. Disclosures All authors: No reported disclosures.

scholarly journals Antibacterial Monoclonal Antibodies Do Not Disrupt the Intestinal Microbiome or Its Function

2020 ◽  
Vol 64 (5) ◽  
Author(s):  
Omari Jones-Nelson ◽  
Andrey Tovchigrechko ◽  
Matthew S. Glover ◽  
Fiona Fernandes ◽  
Udaya Rangaswamy ◽  
...  
Keyword(s):  
Monoclonal Antibodies ◽  
Broad Spectrum ◽  
Gut Microbiome ◽  
Short Chain Fatty Acids ◽  
Intestinal Microbiome ◽  
Bacterial Metabolites ◽  
Minimal Impact ◽  
Fecal Microbiome ◽  
Alpha And Beta Diversity ◽  
Broad Spectrum Antibiotics

ABSTRACT Antibiotics revolutionized the treatment of infectious diseases; however, it is now clear that broad-spectrum antibiotics alter the composition and function of the host’s microbiome. The microbiome plays a key role in human health, and its perturbation is increasingly recognized as contributing to many human diseases. Widespread broad-spectrum antibiotic use has also resulted in the emergence of multidrug-resistant pathogens, spurring the development of pathogen-specific strategies such as monoclonal antibodies (MAbs) to combat bacterial infection. Not only are pathogen-specific approaches not expected to induce resistance in nontargeted bacteria, but they are hypothesized to have minimal impact on the gut microbiome. Here, we compare the effects of antibiotics, pathogen-specific MAbs, and their controls (saline or control IgG [c-IgG]) on the gut microbiome of 7-week-old, female, C57BL/6 mice. The magnitude of change in taxonomic abundance, bacterial diversity, and bacterial metabolites, including short-chain fatty acids (SCFA) and bile acids in the fecal pellets from mice treated with pathogen-specific MAbs, was no different from that with animals treated with saline or an IgG control. Conversely, dramatic changes were observed in the relative abundance, as well as alpha and beta diversity, of the fecal microbiome and bacterial metabolites in the feces of all antibiotic-treated mice. Taken together, these results indicate that pathogen-specific MAbs do not alter the fecal microbiome like broad-spectrum antibiotics and may represent a safer, more-targeted approach to antibacterial therapy.

scholarly journals Loss of Lkb1 impairs Treg function and stability to aggravate graft-versus-host disease after bone marrow transplantation

2019 ◽  
Vol 17 (5) ◽  
pp. 483-495
Author(s):  
Xiuhua Su ◽  
Qianqian Wang ◽  
Wei Guo ◽  
Xiaolei Pei ◽  
Qing Niu ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Graft Versus Host Disease ◽  
Transcriptional Profiling ◽  
Foxp3 Expression ◽  
Loss Of Function ◽  
Hematopoietic Stem ◽  
Host Disease ◽  
Graft Versus Host ◽  
Multiple Defects ◽  
Hematopoietic Reconstitution

Abstract Accumulating evidence suggests that a reduction in the number of Foxp3+ regulatory T cells (Tregs) contributes to the pathogenesis of acute graft-versus-host disease (aGVHD), which is a major adverse complication that can occur after allogeneic hematopoietic stem cell transplantation (allo-HSCT). However, the precise features and mechanism underlying the defects in Tregs remain largely unknown. In this study, we demonstrated that Tregs were more dramatically decreased in bone marrow compared with those in peripheral blood from aGVHD patients and that bone marrow Treg defects were negatively associated with hematopoietic reconstitution. Tregs from aGVHD patients exhibited multiple defects, including the instability of Foxp3 expression, especially in response to IL-12, impaired suppressor function, decreased migratory capacity, and increased apoptosis. Transcriptional profiling revealed the downregulation of Lkb1, a previously identified critical regulator of murine Treg identity and metabolism, and murine Lkb1-regulated genes in Tregs from aGVHD patients. Foxp3 expression in human Tregs could be decreased and increased by the knockdown and overexpression of the Lkb1 gene, respectively. Furthermore, a loss-of-function assay in an aGVHD murine model confirmed that Lkb1 deficiency could impair Tregs and aggravate disease severity. These findings reveal that Lkb1 downregulation contributes to multiple defects in Tregs in human aGVHD and highlight the Lkb1-related pathways that could serve as therapeutic targets that may potentially be manipulated to mitigate aGVHD.

scholarly journals Outcome and Risk Factors of Febrile Episodes Treated with Broad Spectrum Antibiotics and Polyclonal IgM–enriched Immunoglobulin in Pediatric Oncology Hematology Patients: A Retrospective Study

2021 ◽  
Author(s):  
Nicoletta Abram ◽  
Valentina Baretta ◽  
Federico Mercolini ◽  
Massimiliano De Bortoli ◽  
Matteo Chinello ◽  
...  
Keyword(s):  
Risk Factors ◽  
Intensive Care ◽  
Broad Spectrum ◽  
High Titer ◽  
Immunoglobulin M ◽  
Attributable Mortality ◽  
Causative Organism ◽  
Hematopoietic Stem ◽  
Broad Spectrum Antibiotics ◽  
Febrile Episodes

Abstract Objective Preparations with high-titer immunoglobulin-M (HT-IgM) have been used to treat neonatal and adult sepsis as adjuvant to antibiotics. Limited data are available of this use in pediatric oncohematological patients. We retrospectively assessed the characteristics and outcome of febrile episodes treated with broad-spectrum antibiotics and HT-IgM. Methods The study included febrile episodes diagnosed after chemotherapy or hematopoietic stem cell transplantation (HSCT) treated with antibiotics and HT-IgM. Study period was from January 2011 to March 2019. Results Seventy febrile episodes in 63 patients were eligible. In 40% of episodes (n = 28), blood cultures identified a causative organism: Gram-negative (n = 15), Gram-positive (n = 8), polybacterial (n = 4), fungi (n = 1). Twenty-six percent of Gram-negatives were extend spectrum β-lactamase (ESBL)-producers. In 44% of episodes, a deep-organ localization was present, mostly pulmonary. Severe or profound neutropenia, hypotension, and hypoxemia were present in 89, 26, and 21% of episodes, respectively; 20% of episodes required intensive care and 20% of episodes required the use of inotropes. Overall, 90-day mortality was 13% and infection-attributable mortality resulted 8.6%. More than half of the patients received HT-IgM within 24 hours from fever onset. HT-IgM-related allergic reactions occurred in three episodes. Risk factors for 90-day mortality were as follows: hypotension and hypoxemia at fever presentation, admission to intensive care unit (ICU), use of inotropes, presence of deep-organ infection, and escalation of antibiotic therapy within 5 days. Conclusion The combination of broad-spectrum antibiotics and HT-IgM was feasible, tolerated, and promising, being associated with a limited infectious mortality. Further prospective controlled studies are needed to assess the efficacy of this combination over a standard antibiotic approach.

scholarly journals LYG1 Deficiency Attenuates the Severity of Acute Graft-Versus-Host Disease via Skewing Allogeneic T Cells Polarization Towards Treg Cells

2021 ◽  
Vol 12 ◽  
Author(s):  
Huihui Liu ◽  
Zhengyu Yu ◽  
Bo Tang ◽  
Shengchao Miao ◽  
Chenchen Qin ◽  
...  
Keyword(s):  
T Cells ◽  
Graft Versus Host Disease ◽  
Foxp3 Expression ◽  
Hematopoietic Stem ◽  
Host Disease ◽  
Graft Versus Host ◽  
Donor T Cells ◽  
Ifn Γ ◽  
Acute Graft

Acute graft-versus-host disease (aGVHD) is a lethal complication after allogeneic hematopoietic stem cell transplantation. The mechanism involves the recognition of host antigens by donor-derived T cells which induces augmented response of alloreactive T cells. In this study, we characterized the role of a previously identified novel classical secretory protein with antitumor function-LYG1 (Lysozyme G-like 1), in aGVHD. LYG1 deficiency reduced the activation of CD4+ T cells and Th1 ratio, but increased Treg ratio in vitro by MLR assay. By using major MHC mismatched aGVHD model, LYG1 deficiency in donor T cells or CD4+ T cells attenuated aGVHD severity, inhibited CD4+ T cells activation and IFN-γ expression, promoted FoxP3 expression, suppressed CXCL9 and CXCL10 expression, restrained allogeneic CD4+ T cells infiltrating in target organs. The function of LYG1 in aGVHD was also confirmed using haploidentical transplant model. Furthermore, administration of recombinant human LYG1 protein intraperitoneally aggravated aGVHD by promoting IFN-γ production and inhibiting FoxP3 expression. The effect of rhLYG1 could partially be abrogated with the absence of IFN-γ. Furthermore, LYG1 deficiency in donor T cells preserved graft-versus-tumor response. In summary, our results indicate LYG1 regulates aGVHD by the alloreactivity of CD4+ T cells and the balance of Th1 and Treg differentiation of allogeneic CD4+ T cells, targeting LYG1 maybe a novel therapeutic strategy for preventing aGVHD.

scholarly journals Graft Versus Host Disease (GvHD) Is Attenuated By Administration of Pregnancy Specific Glycoproteins through Induction of Immune Tolerance

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 4278-4278
Author(s):  
Karlie R. Sharma ◽  
Shemona Rattila ◽  
Patricia Kiesler ◽  
Angela Ballesteros ◽  
Jian Luo ◽  
...  
Keyword(s):  
T Cells ◽  
Immune Tolerance ◽  
Graft Versus Host Disease ◽  
Foxp3 Expression ◽  
Luciferase Expression ◽  
Hematopoietic Stem ◽  
Host Disease ◽  
Graft Versus Host ◽  
Donor T Cells ◽  
Tgfβ Receptor

Abstract Hematopoietic stem cell transplantation is curative for many disorders; however, it can be associated with significant morbidity and mortality, often as a result of graft versus host disease (GvHD). GvHD is an immune mediated reaction in which donor T-cells recognize the host antigens as foreign, causing donor T-cells to proliferate and attack host tissues. Establishment of a tolerogenic immune environment while preserving immune response to infectious agents and malignancy is required for successful bone marrow transplantationand GvHD presents a significant obstacle to this. Pregnancy specific glycoproteins (PSGs) are synthesized by the placenta at the onset of pregnancy and are believed to play a role in maintaining a tolerogenic immune environment to prevent rejection of the fetus by the maternal immune system. Two specific PSG proteins, PSG1 and PSG9, are of particular note as they have both been shown to be involved in pathways devoted to induction of immune tolerance. Both PSG1 and PSG9 are involved in activation of transforming growth factor-β (TGFβ), a cytokine essential to suppression of inflammatory T-cells and important for differentiation of tolerance inducing CD4+ CD25+ FoxP3+ regulatory T-cells (Tregs), a cell population shown to be important in the prevention of GvHD. We thus hypothesized that PSG1 and PSG9 (PSG1/9) could be used to treat or prevent GvHD by inducing immune tolerance through TGFβ. Using surface plasmon resonance (SPR) analysis, we have shown that PSG1/9 bind directly to the latency associated peptide (LAP), a protein that confers latency to mature TGFβ, effectively blocking binding of TGFβ to its receptors. Further, bioassays and ELISA data show an increase in the levels of bioactive TGFβ after treatment with PSG1/9, indicating that these proteins have a role in TGFβ activation through their interaction with LAP. In vitro data using naïve mouse T-cells showed that upon treatment with PSG1, there was a significant increase of CD4+ CD25+ cells expressing FoxP3 (18%±1.5; n=3) compared to only 2% in untreated controls (2%±0.4; n=6) (p<0.0001). Similarly, PSG9 treatment also increased FoxP3 expression (11%±2.8; n=3) over controls (p<0.0001). The increase in FoxP3 expression was also observed upon treatment of primary naïve human T-cells with both PSG1 and PSG9 (PSG1, p=0.0073; PSG9, p=0.0028). When a TGFβ receptor inhibitor was added to cell culture, the increase in FoxP3 expression was effectively blocked, further supporting the hypothesis that PSG1/9 induce expression of FoxP3+ Tregs through regulation of TGFβ. As IL-2 is important for the stability and differentiation of Tregsin vivo and its transcription is suppressed by TGFβ, we performed bioassays on CD4+ naïve T-cells with no added IL-2. We observed that in the absence of added IL-2, treatment with PSG1/9 resulted in an inhibition of IL-2 secretion by activated CD4+ T-cells, and there was no increase in the number and percentage of FoxP3 expressing cells. SBE-luc mice, which express luciferase in response to activation of the TGFβ-SMAD pathway, exhibited significantly increased luciferase expression in the abdomen when injected intraperitoneally with PSG1. This supports the idea that PSG1 induces expression of FoxP3 through the TGFβ receptor pathway in vivo. Finally, using a murine model of GvHD, we observed that mice receiving PSG1 had reduced numbers of infiltrating inflammatory CD3+ T-cells in the colon and showed a marked improvement physically and histologically over untreated controls. In addition, PSG1 treated mice had significantly higher expression of FoxP3 in CD4+ CD25+ splenic cells (30%±9.6; n=4) when compared to untreated GvHD controls (8.6%±3.2; n=3) (p=0.0287). Currently, we are studying the cytokine profiles of mice treated with PSG to determine the efficacy of PSG1/9 in reducing the release of pro-inflammatory cytokines during GvHD. Overall, our data suggests that PSG1/9 induce immune tolerance in GvHD and may be a future treatment option for these patients. Disclosures No relevant conflicts of interest to declare.

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