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The Composite Immune Risk Score predicts overall survival after allogeneic hematopoietic stem cell transplantation: A retrospective analysis of 1838 cases
Cao, Y., Gong, X., Feng, Y., Wang, M., Hu, Y., Liu, H., Liu, X., Qi, S., Ji, Y., Liu, F., et al
American journal of hematology. 2023
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Abstract
There has been little consensus on how to quantitatively assess immune reconstitution after hematopoietic stem cell transplantation (HSCT) as part of the standard of care. We retrospectively analyzed 11 150 post-transplant immune profiles of 1945 patients who underwent HSCT between 2012 and 2020. 1838 (94.5%) of the cases were allogeneic HSCT. Using the training set of patients (n = 729), we identified a composite immune signature (integrating neutrophil, total lymphocyte, natural killer, total T, CD4(+) T, and B cell counts in the peripheral blood) during days 91-180 after allogeneic HSCT that was predictive of early mortality and moreover simplified it into a formula for a Composite Immune Risk Score. When we verified the Composite Immune Risk Score in the validation (n = 284) and test (n = 391) sets of patients, a high score value was found to be associated with hazard ratios (HR) of 3.64 (95% C.I. 1.55-8.51; p = .0014) and 2.44 (95% C.I., 1.22-4.87; p = .0087), respectively, for early mortality. In multivariate analysis, a high Composite Immune Risk Score during days 91-180 remained an independent risk factor for early mortality after allogeneic HSCT (HR, 1.80; 95% C.I., 1.28-2.55; p = .00085). In conclusion, the Composite Immune Risk Score is easy to compute and could identify the high-risk patients of allogeneic HSCT who require targeted effort for prevention and control of infection.
PICO Summary
Population
Post-transplant immune profiles of 1945 patients who underwent HSCT at a single centre in China between 2012 and 2020 (n=11 150)
Intervention
Identification of a composite immune signature (integrating neutrophil, total lymphocyte, natural killer, total T, CD4(+) T, and B cell counts in the peripheral blood) during days 91-180 after allogeneic HSCT to predict early mortality and produce a formula for a Composite Immune Risk Score.
Comparison
validation (n = 284) and test (n = 391) sets
Outcome
A high score value was found to be associated with hazard ratios (HR) of 3.64 (95% C.I. 1.55-8.51) and 2.44 (95% C.I., 1.22-4.87) for early mortality in the validation and test cohorts respectively. In multivariate analysis, a high Composite Immune Risk Score during days 91-180 remained an independent risk factor for early mortality after allogeneic HSCT (HR, 1.80; 95% C.I., 1.28-2.55).
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The frequencies of lymphocyte subsets on "day 30" correlate with the clinical outcome of pediatric hematopoietic stem cell transplantation
Yao, Y., Li, B., Li, J., Yao, D., Ling, J., Hu, Y., Fan, L., Wan, L., Kong, L., Xiao, P., et al
Immunology letters. 2023
Abstract
We aimed to determine the relationship between lymphocyte subsets on day 30 (D30) and prognosis after allogeneic hematopoietic stem cell transplantation (allo-HSCT) in children. We retrospectively examined the clinical outcomes and lymphocyte subsets on D30 after allo-HSCT in 115 pediatric patients at the Children's Hospital of Soochow University between January 2016 and June 2019. Measurements were performed using flow cytometry on D30. Lymphocyte subsets were compared among the umbilical cord blood (UCB) (n=22), HLA-matched sibling donor (MSD) (n=14), haploidentical donor transplantation (HID) (n=57), and unrelated donor transplantation (UD) (n=22) groups. The relationships between the frequencies and counts of lymphocyte subsets and clinical outcomes were analyzed. T and B cell counts were the highest in the MSD group compared to the other groups, and natural killer cell counts were the highest in the UCB group. Lymphocyte subsets on D30 after allo-HSCT were correlated with the occurrence of acute (aGVHD) and chronic graft versus host disease (cGVHD). A high frequency of B cells (≥4.65%) was associated with the development of severe aGVHD. High frequencies of CD4(+) T (≥10.25%) were correlated with extensive cGVHD. Moreover, a high frequency of CD4(+) T cells (≥9.80%) was correlated with GVHD-free and failure-free survival (GFFS) after allo-HSCT. However, on D30, there were no statistically significant correlations between viral infections and lymphocyte subsets. The frequencies of lymphocyte subsets on D30 after allo-HSCT are good indicators of prognosis after allo-HSCT in children.
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Nanopore-Targeted Sequencing Improves the Diagnosis and Treatment of Patients with Serious Infections
Zhang, Y., Lu, X., Tang, L. V., Xia, L., Hu, Y.
mBio. 2023;14(1):e0305522
Abstract
Serious infections are characterized by rapid progression, poor prognosis, and difficulty in diagnosis. Recently, a new technique known as nanopore-targeted sequencing (NTS) was developed that facilitates the rapid and accurate detection of pathogenic microorganisms and is extremely suitable for patients with serious infections. The aim of our study was to evaluate the clinical application of NTS in the diagnosis and treatment of patients with serious infections. We developed an NTS technology that could detect microorganisms within a 6-h window based on the amplification of the 16S rRNA gene of bacteria, the internal transcribed spacer region of fungi, and the rpoB gene of Mycobacterium. The NTS detection results were compared with those of blood cultures and anal swabs from 50 patients with blood diseases suffering serious infections. The patient's condition before and after NTS was compared. The response rate and the infection-related mortality after the adjustment of antibiotics based on NTS were calculated. The positivity rate of pathogens was highest in NTS (90%), followed by blood culture (32.6%) and anal swabs (14.6%). After adjusting antibiotics for bacteria and fungi detected by NTS, the patients' condition improved significantly. Moreover, the response rate of anti-infective treatment based on NTS was 93.02% (40/43), and infection-related mortality was reduced to 0. NTS is an effective method to identify pathogens in the blood specimens of patients with serious infections and can guide anti-infection treatment and reduce infection-related mortality. IMPORTANCE We introduce the application of NTS in blood samples of patients with serious infections and expound the efficiency and accuracy of NTS in detecting pathogenic microorganisms. Our work builds on the considerable interest of the scientific community in the management of serious infection. This issue is becoming more pressing, especially since the incidence of blood diseases is increasing year by year and hematopoietic stem cell transplantation (HSCT) has been widely used in benign and malignant blood diseases in recent years. The infection progression of these patients is faster, and the study further demonstrates the effectiveness of NTS in guiding the diagnosis and treatment of patients with severe infections. We firmly believe that this method will guide clinicians to adjust anti-infection strategies and bring significant benefits to patients, and our study will have implications for the future clinical application of NTS in all kinds of patients with serious infections.
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Clinical value of plasma and peripheral blood mononuclear cells Epstein-Barr Virus DNA dynamics on prognosis of allogeneic stem cell transplantation
Zhou, X., Lu, X., He, J., Xu, Z., Li, Q., Ye, P., Zhong, Z., Shi, W., Yan, H., You, Y., et al
Frontiers in Cellular and Infection Microbiology. 2022;12:980113
Abstract
The application of intracellular and extracellular Epstein-Barr virus (EBV) DNA in allogeneic hematopoietic stem cell transplantation (allo-HSCT) has been poorly characterized. We conducted a combined prospective-retrospective study of 300 patients who underwent allo-HSCT between 2016 to 2019 in our center and monitored for EBV DNA within the first year after HSCT. Combining the optimal cut-off value of EBV DNA load (7.3×10(4) copies/10(6) cells) in peripheral blood mononuclear cells (PBMCs) and qualitative detection in plasma (400 copies/mL) allowed for the better differentiation of EBV-related posttransplant lymphoproliferative disorders (EBV-PTLD), with increased sensitivity (100%) and specificity (86%), and provided the effective risk stratification of EBV DNA level according to their impact on transplant outcomes. By multivariate analysis, patients with intermediate-level of EBV DNA load (low EBV DNA load in PBMCs or high load in PBMCs but negative in plasma) was associated with superior overall survival (HR 1.92, 95% CI 1.03-3.57, p=0.039) and lower transplant-related mortality (HR 3.35, 95% CI 1.31-8.58, p=0.012) compared to those with high-level (high load in PBMCs and positive in plasma). Notably, high EBV-level group had poor reconstitution of CD4+ and CD8+T cells, and both low and high EBV-level groups showed abnormally increase in IL-10 level within one year. Additionally, patients with peak EBV DNA load in PBMCs during 3-12 months had a higher incidence of chronic graft versus host disease (GVHD) than those within 3 months post transplantation (17.4% vs 13.7%, p=0.029). Collectively, EBV DNA in PBMCs can synergistically predict the risk of EBV-PTLD and GVHD. The intermediate-level of EBV DNA presented in plasma and PBMCs might contribute to a better reconstitution of T cells associated with favorable prognosis of allo-HSCT.
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Association between CD34(+) and CD3(+) T-cells in allogeneic grafts and acute graft-versus-host disease in children undergoing allogeneic hematopoietic stem cell transplantation: A single-center study
Yao, D., Li, B., Chu, X., Pan, J., Meng, L., Hu, Y., Gao, L., Li, J., Tian, Y., Hu, S.
Transplant immunology. 2022;77:101779
Abstract
BACKGROUND Acute graft-versus-host disease (aGVHD) is a major complication of allogeneic hematopoietic stem cell transplantation (allo-HSCT). We examined the association between the composition of the cell subsets present in allogeneic grafts (allografts) and the occurrence and severity of aGVHD in pediatric patients. METHODS We retrospectively analyzed 80 consecutive pediatric patients undergoing allo-HSCT at our center. RESULTS Both univariate and multivariate analyses showed that the number of CD34(+) and CD3(+) T-cells in allografts were the two highest risk factors associated with II-IV aGVHD. Using receiver operating characteristic analysis, the cutoff levels of the allo-HSCT cell doses were used to divide the recipients into low-dose and high-dose groups. The 100-day cumulative incidence of II-IV aGVHD in the high-dose CD34(+) and CD3(+) T-cells group was significantly higher than that of the low-dose group (CD34(+): 57% vs. 29%, p = 0.009; CD3(+): 63% vs. 18%, p < 0.001). No other clinical factors or cell subsets correlated with aGVHD incidence. CONCLUSIONS Our analysis indicates that the CD34(+) and CD3(+) T-cell numbers in the allografts could be the risk factors for the development of severe aGVHD (level II-IV). Further studies should aim to optimize the critical number of CD34(+) and CD3(+) T-cells to reduce the risk of severe aGVHD occurrence in pediatric patients.
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Low levels of plasmacytoid dendritic cells at engraftment are a valuable prognostic indicator in children receiving allogeneic hematopoietic stem cell transplantation
Li, B., Meng, L., Tian, Y., Ling, J., Hu, Y., Lu, Q., Gao, L., Wu, S., Zhang, Y., Hu, S.
Transplantation and cellular therapy. 2021
Abstract
BACKGROUND Early prediction and intervention are known to be critical for acute graft-versus-host disease (aGvHD) prevention and treatment. Significant progress has been made in the development of human plasma biomarkers for the risk stratification of aGvHD severity. Whether donor-derived immune cells may predict the occurrence of severe aGvHD early after allogeneic hematopoietic stem cell transplantation (allo-HSCT) remains poorly understood. OBJECTIVE The objective of this study is to evaluate the results of allo-HSCT in pediatric patients with different counts and frequency of dendritic cells (DCs) subsets at engraftment in pediatric patients within the Children's Hospital of Soochow University. STUDY DESIGN This is a retrospective study. A total of 45 patients as a discovery cohort were enrolled from March 2018 to December 2018 within the Children's Hospital of Soochow University. The validation cohort (30 patients) was enrolled from December 2019 to May 2020. Plasma samples collected from 2016 to 2018 were used for testing ST2 and Reg3a in pediatric patients undergoing allo-HSCT. RESULTS Patients with grade II-IV aGvHD (n=18, termed severe aGvHD) showed 3- and 6-fold fewer frequency and numbers, respectively, of plasmacytoid dendritic cells (pDCs) in the peripheral blood (PB) at the engraftment time than patients with grade 0-I aGvHD (n=27, termed no/mild aGvHD). Using the receiver operating characteristic (ROC) curve analysis, we identified the threshold of pDC level at 0.3 cells/µl as a cutoff to evaluate the difference in patients with high (>0.3 cells/µl) versus low (<0.3 cells/µl) pDC counts. Of these 45 patients, 21 (46.7%) patients had high pDCs and 24 (53.3%) patients showed low pDCs. Patients with low pDCs at the engraftment time had a significantly higher probability of developing severe aGvHD (p<0.05). The sensitivity of distinguishing severe aGvHD from no/mild aGvHD was 75% and the specificity was 94%. Additionally, low pDC patients had higher transplant-related mortality compared to high pDC patients (12.5% versus 0%). Using an additional cohort of 30 allo-HSCT patients, we validated this observation. CONCLUSION Our findings identify that donor pDC counts in PB at the engraftment time are a valuable biomarker for predicting severe aGvHD in pediatric patients undergoing allo-HSCT.
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Improved survival for young acute leukemia patients following a new donor hierarchy for allogeneic hematopoietic stem cell transplantation: a phase III randomized controlled study
Zhang, M., Xiao, H., Shi, J., Tan, Y., Zhao, Y., Yu, J., Lai, X., Hu, Y., Zheng, W., Luo, Y., et al
American journal of hematology. 2021
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Editor's Choice
Abstract
The aim of our study was to evaluate the most optimal donor for young acute leukemia (AL) patients with multiple donors available for allogeneic hematopoietic stem cell transplantation (allo-HSCT), including HLA-matched sibling donors (MSDs), HLA-matched unrelated donors (URDs), haploidentical parental donors (HPDs), and haploidentical sibling donors (HSDs). From March 2008 to December 2016, 430 AL patients = 35?years of age were included in the discovery, retrospective study. Patients who received transplantation from a MSD or a HSD had better 5-year OS rates compared with patients who received transplantation from a URD or a HPD. A superior graft-versus-leukemia effect was observed for high-risk patients undergoing HSD-HSCT with a lower relapse rate (P = .014) and a higher disease-free survival (DFS) rate (P = .029) compared with those undergoing MSD-HSCT. Outcomes of high-risk patients receiving an URD or HPD were equivalent. For intermediate/standard-risk patients, either a MSD or HSD may be the front-line donor selection with comparable outcomes. URDs were preferred over HPDs with reduced non-relapse mortality and higher overall survival (OS) and DFS rates. We further conducted an independent prospective randomized study to evaluate the survival advantage with the new donor hierarchy. Two hundred and fifty patients were randomly assigned to follow our new donor hierarchy or the traditional donor hierarchy at a 2:1 ratio. The new donor hierarchy contributed to significantly superior 2-year OS and DFS rates (OS: 76.2% vs. 67.8%, P = .046; DFS: 71.8% vs. 64.5%, P = .039). This article is protected by copyright. All rights reserved.
PICO Summary
Population
Patients with acute leukaemia aged </=35 years undergoing allogeneic transplantation in a single centre in China, with multiple donors available (Retrospective cohort: n=430; RCT cohort: n=250)
Intervention
New donor hierarchy based on results from retrospective cohort (n=166): haploidentical sibling donor (HSD, n=91) then matched sibling donor (MSD, n=38); then matched unrelated donor (URD, n=9) or haploidentical donor (HPD, n=28)
Comparison
Traditional donor hierarchy (n=84): HLA-matched sibling donors (n=16) followed by matched unrelated donors (n=29), then other donors (haploidentical donors or unrelated cord blood, n=39)
Outcome
In the discovery, retrospective study, patients who received transplantation from a MSD or a HSD had better 5-year OS rates compared with patients who received transplantation from a URD or a HPD. In the RCT, a superior graft-versus-leukemia effect was observed for high-risk patients undergoing HSD-HSCT with a lower relapse rate and a higher disease-free survival (DFS) rate compared with those undergoing MSD-HSCT. Outcomes of high-risk patients receiving an URD or HPD were equivalent. In the RCT cohort, the new donor hierarchy contributed to significantly superior 2-year OS and DFS rates (OS: 76.2% vs. 67.8%; DFS: 71.8% vs. 64.5%).
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Risk factors of non-invasive ventilation failure in hematopoietic stem-cell transplantation patients with acute respiratory distress syndrome
Shen, J., Hu, Y., Zhao, H., Xiao, Z., Zhao, L., Du, A., An, Y.
Therapeutic advances in respiratory disease. 2020;14:1753466620914220
Abstract
BACKGROUND Non-invasive ventilation (NIV) was one of the first-line ventilation supports for hematopoietic stem-cell transplantation (HSCT) patients with acute respiratory distress syndrome (ARDS). Successful NIV may avoid need for intubation. However, the influence NIV failure had on patients' outcome and its risk factors were hardly known. METHODS In this retrospective observational study, we reported risk factors and incidence of NIV failure in HSCT patients who were admitted to the Intensive Care Unit (ICU) with a diagnosis of ARDS and supported with mechanical ventilation, in a 5-year period. Patient outcomes, such as ventilator-free days, ICU-free days, and ICU mortality were also reported. RESULTS Of all the 94 patients included, 70 patients were initially supported with NIV. NIV failure occurred in 44 (63%) patients. Male sex, elevated serum galactomannan (GM) test, (1-3)-beta-D-glucan (BG) assay, or elevated serum creatinine level were risk factors for NIV failure. When compared with the NIV success group, failure of NIV was associated with much fewer ICU-free days (22 versus 0, p < 0.001, Cohen's d = 0.62) and higher ICU mortality (9.5% versus 75.5%, p < 0.001, Pearson's r = 0.75). There was no difference in ICU-free days, ventilator-free days and ICU mortality between NIV failure and initial invasive mechanical ventilation (IMV) groups. Patients who failed in NIV support had a higher ICU mortality (75.5%) than those who succeeded (9.5%). CONCLUSION In a small cohort of HSCT patients with mainly moderate severity of ARDS, male patients with elevated serum GM/BG test or serum creatinine level had a higher risk of NIV failure. Both NIV failure and initial IMV groups were characterized by high mortality rate and extremely low ICU-free days and ventilator-free days; failure of NIV support may further aggravate patient prognosis. The reviews of this paper are available via the supplemental material section.
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Cytotoxicity of Donor Natural Killer Cells to Allo-Reactive T Cells Are Related With Acute Graft-vs.-Host-Disease Following Allogeneic Stem Cell Transplantation
Sheng, L., Mu, Q., Wu, X., Yang, S., Zhu, H., Wang, J., Lai, Y., Wu, H., Sun, Y., Hu, Y., et al
Frontiers in immunology. 2020;11:1534
Abstract
Objectives: The mechanism and immunoregulatory role of human natural killer (NK) cells in acute graft-vs.-host-disease (aGVHD) remains unclear. This study quantitatively analyzed the cytotoxicity of donor NK cells toward allo-reactive T cells, and investigated their relationship with acute GVHD (aGVHD). Methods: We evaluated NK dose, subgroup, and receptor expression in allografts from 98 patients who underwent allogeneic hematopoietic stem cell transplantation (allo-HSCT). A CD107a degranulating assay was used as a quantitative detection method for the cytotoxic function of donor NK cells to allo-reactive T cells. In antibody-blocking assay, NK cells were pre-treated with anti-DNAM-1(CD226), anti-NKG2D, anti-NKP46, or anti-NKG-2A monoclonal antibodies (mAbs) before the degranulating assay. Results: NK cells in allografts effectively inhibited auto-T cell proliferation following alloantigen stimulation, selectively killing alloantigen activated T cells. NKG2A(-) NK cell subgroups showed higher levels of CD107a degranulation toward activated T cells, when compared with NKG2A(-) subgroups. Blocking NKG2D or CD226 (DNAM-1) led to significant reductions in degranulation, whereas NKG2A block resulted in increased NK degranulation. Donor NK cells in the aGVHD group expressed lower levels of NKG2D and CD226, higher levels of NKG2A, and showed higher CD107a degranulation levels when compared with NK cells in the non-aGVHD group. Using univariate analysis, higher NK degranulation activities in allografts (CD107a(high)) were correlated with a decreased risk in grade I-IV aGVHD (hazard risk [HR] = 0.294; P < 0.0001), grade III-IV aGVHD (HR = 0.102; P < 0.0001), and relapse (HR = 0.157; P = 0.015), and improved overall survival (HR = 0.355; P = 0.028) after allo-HSCT. Multivariate analyses showed that higher NK degranulation activities (CD107a(high)) in allografts were independent risk factors for grades, I-IV aGVHD (HR = 0.357; P = 0.002), and grades III-IV aGVHD (HR = 0.13; P = 0.009). Conclusions: These findings reveal that the degranulation activity of NK in allografts toward allo-activated T cells was associated with the occurrence and the severity of aGVHD, after allogeneic stem cell transplantation. This suggested that cytotoxicity of donor NK cells to allo-reactive T cells have important roles in aGVHD regulation.
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Determining whether prophylactic antiviral treatment is necessary in HBsAg-negative/HBcAb-positive patients receiving allogeneic hematopoietic stem cell transplantation
Zhang, A., Wu, Y., Tan, Y., Shi, J., Zhao, Y., Hu, Y., Yu, J., Zheng, W., Lai, X., Zhang, M., et al
Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation. 2020
Abstract
BACKGROUND The incidence of hepatitis B virus (HBV) infection is high in the Asian population. Increasing attention is being paid to the risk of HBV reactivation in hepatitis B core antibody-positive (HBcAb(+)) patients during immunosuppressive therapy. Knowledge of HBV reactivation in hematopoietic stem cell transplantation (HSCT) is limited. Moreover, the effect of hepatitis B surface antibody (HBsAb) on HBV reactivation in HBcAb(+) patients during HSCT remains uncertain. We sought to investigate the role of HBsAb and the necessity of prophylactic antiviral treatment in hepatitis B surface antigen-negative (HBsAg(-))/HBcAb(+) patients during HSCT. METHODS We classified 665 HBsAg(-) HSCT recipients into 4 groups: HBcAb(-)HBsAb(-) (n=189), HBcAb(-)HBsAb(+) (n=176), HBcAb(+)HBsAb(-) (n=49), and HBcAb(+)HBsAb(+) (n=251). RESULTS HBV reactivation was identified in 16 patients after HSCT. The median HBV reactivation time was 645 days (range 455-1957) after transplantation. The cumulative HBV reactivation rate was significantly higher in the HBcAb(+)HBsAb(-) group as compared to the HBcAb(+)HBsAb(+), HBcAb(-)HBsAb(-), and HBcAb(-)HBsAb(+) group, respectively (p<0.001). Notably, the risk of HBV reactivation was significantly higher in the HBcAb(+)HBsAb(-) group than that in the HBcAb(+)HBsAb(+) group (p=0.007, hazard ratio [HR]=4.750, 95% confidence interval [CI]=1.531-14.737). CONCLUSIONS Our results indicate a protective role of HBsAb in HBV-resolved patients receiving HSCT and conclude that prophylactic anti-hepatitis B virus treatment may not be mandatory for HBsAg(-), HBcAb(+)HBsAb(+) patients following HSCT. The surveillance protocol of intense follow-up early (HBV DNA and HBsAg monthly) may not be required.