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1.
Influence of invasive aspergillosis during acute leukaemia treatment on survival after allogeneic stem cell transplantation: a prospective study of the EBMT Infectious Diseases Working Party
Penack, O., Tridello, G., Salmenniemi, U., Martino, R., Khanna, N., Perruccio, K., Fagioli, F., Richert-Przygonska, M., Labussière-Wallet, H., Maertens, J., et al
EClinicalMedicine. 2024;67:102393
Abstract
BACKGROUND Infections are the main reason for mortality during acute leukaemia treatment and invasive aspergillosis (IA) is a major concern. Allogeneic stem cell transplantation (alloSCT) is a standard therapy and often is the only live-saving procedure in leukaemia patients. The profound immunodeficiency occurring after alloSCT led to high IA-associated mortality in the past. Therefore, patients with IA were historically considered transplant-ineligible. Recently, there has been improvement of anti-fungal management including novel anti-fungal agents. As a result, more leukaemia patients with IA are undergoing alloSCT. Outcome has not been prospectively assessed. METHODS We performed a prospective study in acute leukaemia patients undergoing alloSCT to analyse the impact of a prior history of probable or proven IA (pre-SCT IA). The primary endpoint was 1-year non-relapse mortality (NRM). Relapse free survival and overall survival were analysed as secondary endpoints. FINDINGS 1439 patients were included between 2016 and 2021. The incidence of probable or proven pre-SCT IA was 6.0% (n = 87). The cumulative incidence of 1-year NRM was 17.3% (95% CI 10.2-26.0) and 11.2% (9.6-13.0) for patients with and without pre-SCT IA. In multivariate analyses the hazard ratio (HR) for 1-year NRM was 2.1 (1.2-3.6; p = 0.009) for patients with pre-SCT IA. One-year relapse-free survival was inferior in patients with pre-SCT IA (59.4% [48.3-68.9] vs. 70.4 [67.9-72.8]; multivariate HR 1.5 [1.1-2.1]; p = 0.02). Consequently, 1-year overall survival was lower in patients with pre-SCT IA (68.8% [57.8-77.4] vs. 79.0% [76.7-81.1]; multivariate HR 1.7 [1.1-2.5]; p = 0.01). INTERPRETATION Pre-SCT IA remains to be significantly associated with impaired alloSCT outcome. On the other hand, more than two thirds of patients with pre-SCT IA were alive at one year after alloSCT. IA is not anymore an absolute contraindication for alloSCT because the majority of patients with IA who undergo alloSCT benefit from this procedure. FUNDING There was no external funding source for this study.
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2.
Disparities in CMV infection rates by race and ethnicity among pediatric allogeneic hematopoietic cell transplant recipients at a single center
Boge, C. L. K., McDonough, M. H., Newman, A. M., Blumenstock, J., Elgarten, C. W., Freedman, J. L., Olson, T. S., Li, Y., Fisher, B. T.
Transplantation and cellular therapy. 2024
Abstract
BACKGROUND Previous literature has reported cytomegalovirus (CMV) infection rate disparities between race and ethnicity groups of hematopoietic cell transplant (HCT) recipients. Because race and ethnicity categorizations are social constructs unlikely to affect biological systems, it is likely there are covariates on the pathway to CMV detection, known as mediators, which would explain the observed disparity. Recent developments in mediation analysis methods enable the analysis of time-to-event outcomes, allowing an investigation of these disparities to also consider the timing of infection detection relative to HCT. OBJECTIVE This study aimed to explore whether racial and ethnic CMV infection disparities existed within a population of HCT recipients at our center and whether clinical covariates explained any observed association. STUDY DESIGN The study includes all allogeneic HCTs performed at the Children's Hospital of Philadelphia January 2004-April 2017 where subjects were CMV polymerase chain reaction (PCR) negative pre-transplant, had known donor/recipient CMV serology, and under blood PCR CMV surveillance. Subjects were followed for 100 days post-HCT. Accelerated failure time models using subject's reported race/ethnicity, dichotomized into non-Hispanic White (NHW) and not NHW, as exposure and time to CMV detection as outcome examined whether selected clinical factors (donor/recipient CMV serostatus, recipient age, transplant indication, hematopoietic cell source, match quality) mediated any identified exposure-outcome association. RESULTS The analysis included 348 HCT episodes from 335 subjects; 86 episodes (24.7%) detected CMV via PCR testing. The accelerated failure time model without mediators estimated non-NHW subjects had fewer CMV-free survival days (Time Ratio: 0.21, 95% Confidence Interval: 0.10-0.44). Any hypothesized mediator mediated at most 5% of the total association between race/ethnicity and time to CMV detection. CONCLUSION Non-NHW HCT recipients had fewer CMV-free survival days than NHW recipients; none of the clinical factors hypothesized to mediate this association accounted for a significant component of total association. Further research should focus on non-clinical factors influenced by systemic racism to better understand its effect on CMV infection among HCT recipients.
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3.
HHV-6B detection and host gene expression implicate HHV-6B as pulmonary pathogen after hematopoietic cell transplant
Hill, J. A., Lee, Y. J., Vande Vusse, L. K., Xie, H., Chung, E. L., Waghmare, A., Cheng, G. S., Zhu, H., Huang, M. L., Hill, G. R., et al
Nature communications. 2024;15(1):542
Abstract
Limited understanding of the immunopathogenesis of human herpesvirus 6B (HHV-6B) has prevented its acceptance as a pulmonary pathogen after hematopoietic cell transplant (HCT). In this prospective multicenter study of patients undergoing bronchoalveolar lavage (BAL) for pneumonia after allogeneic HCT, we test blood and BAL fluid (BALF) for HHV-6B DNA and mRNA transcripts associated with lytic infection and perform RNA-seq on paired blood. Among 116 participants, HHV-6B DNA is detected in 37% of BALs, 49% of which also have HHV-6B mRNA detection. We establish HHV-6B DNA viral load thresholds in BALF that are highly predictive of HHV-6B mRNA detection and associated with increased risk for overall mortality and death from respiratory failure. Participants with HHV-6B DNA in BALF exhibit distinct host gene expression signatures, notable for enriched interferon signaling pathways in participants clinically diagnosed with idiopathic pneumonia. These data implicate HHV-6B as a pulmonary pathogen after allogeneic HCT.
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4.
The indirect effects of CMV reactivation on patients following allogeneic hematopoietic stem cell transplantation: an evidence mapping
Wu, X., Ma, X., Song, T., Liu, J., Sun, Y., Wu, D.
Annals of hematology. 2024
Abstract
Cytomegalovirus (CMV) reactivation following allogeneic hematopoietic stem cell transplantation (allo-HSCT) remains a challenging problem, and the impact on the risk of overall mortality (OM) and non-relapse mortality (NRM) in patients following allo-HSCT is still controversial. Utilizing the evidence mapping method, we aimed to assess the effect of CMV infection on outcomes of patients post-transplantation and identify research gaps through systematic reviews (SRs) and clinical studies. PubMed, EMBASE, Web of Science, and Cochrane library databases were searched from inception until 5 July 2022 to identify relevant literature. After systematic literature screening and data extraction, evidence mapping of the effects of CMV reactivation on patients post-allo-HSCT was conducted. Three SRs and 22 clinical studies were included. In one SR, CMV reactivation was associated with an increased risk of mortality (HR 1.46; 95% CI, 1.24-1.72; P ≤ 0.001). In two SRs, CMV reactivation was associated with NRM. One SR reported CMV reactivation was potentially associated with significant protection against relapse in patients with acute myelocytic leukemia (AML), but no significant correlation with graft-versus-host disease (GVHD) was found. Lastly, in one SR CMV reactivation significantly increased the risk of invasive fungal disease (IFD). Most clinical articles reported that CMV reactivation increased the risk of renal dysfunction, poor graft function, re-hospitalization, and bacterial infections. CMV reactivation following allo-HSCT is associated with an increased risk of OM, NRM, IFD, and renal dysfunction, as well as a reduced risk of relapse in patients with AML.
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5.
Inter and intra-host diversity of RSV in hematopoietic stem cell transplant adults with normal and delayed viral clearance
Avadhanula, V., Agustinho, D. P., Menon, V. K., Chemaly, R. F., Shah, D. P., Qin, X., Surathu, A., Doddapaneni, H., Muzny, D. M., Metcalf, G. A., et al
Virus evolution. 2024;10(1):vead086
Abstract
Respiratory syncytial virus (RSV) infection in immunocompromised individuals often leads to prolonged illness, progression to severe lower respiratory tract infection, and even death. How the host immune environment of the hematopoietic stem cell transplant (HCT) adults can affect viral genetic variation during an acute infection is not understood well. In the present study, we performed whole genome sequencing of RSV/A or RSV/B from samples collected longitudinally from HCT adults with normal (<14 days) and delayed (≥14 days) RSV clearance who were enrolled in a ribavirin trial. We determined the inter-host and intra-host genetic variation of RSV and the effect of mutations on putative glycosylation sites. The inter-host variation of RSV is centered in the attachment (G) and fusion (F) glycoprotein genes followed by polymerase (L) and matrix (M) genes. Interestingly, the overall genetic variation was constant between normal and delayed clearance groups for both RSV/A and RSV/B. Intra-host variation primarily occurred in the G gene followed by non-structural protein (NS1) and L genes; however, gain or loss of stop codons and frameshift mutations appeared only in the G gene and only in the delayed viral clearance group. Potential gain or loss of O-linked glycosylation sites in the G gene occurred both in RSV/A and RSV/B isolates. For RSV F gene, loss of N-linked glycosylation site occurred in three RSV/B isolates within an antigenic epitope. Both oral and aerosolized ribavirin did not cause any mutations in the L gene. In summary, prolonged viral shedding and immune deficiency resulted in RSV variation, especially in structural mutations in the G gene, possibly associated with immune evasion. Therefore, sequencing and monitoring of RSV isolates from immunocompromised patients are crucial as they can create escape mutants that can impact the effectiveness of upcoming vaccines and treatments.
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6.
Cytomegalovirus Reactivation as a Risk Factor for All-Cause Mortality in Children Undergoing Hematopoietic Stem Cell Transplantation: Experience Over Two Decades from a Tertiary Referral Center in India
Chakraborty, S., Swaminathan, V. V., Ganesan, K., Duraisamy, S., Meena, S., Jayakumar, I., Krishna, V., Uppuluri, R., Raj, R.
Indian journal of hematology & blood transfusion : an official journal of Indian Society of Hematology and Blood Transfusion. 2024;40(1):91-96
Abstract
The aim of the study was to analyse the burden of cytomegalovirus (CMV) disease in children undergoing hematopoietic stem cell transplantation (HSCT) and its correlation with all-cause mortality. We performed a retrospective study in children up to 18 years of age who underwent allogeneic HSCT between February 2002 to December 2021 in the pediatric blood and marrow transplantation unit. A total of 1035 patients were included where five hundred forty-three (52.4%) patients underwent matched family donor (MFD) HSCT, 213 (20.5%) underwent matched unrelated donor (MUD) HSCT; 279 (26.9%) underwent haploidentical HSCT (T cell replete in 213 and T cell depleted in 66 patients). CMV reactivation was documented in 258 (24.9% patients). CMV was seen in 39 (7.2%) MFD, 77 (36.1%) MUD, 106 T cell replete (49.7%) and 36 T cell depleted (54.5%) transplants. CMV reactivation was predominantly documented in those where donor and recipient were positive (D + /R +) for CMV serostatus (77%)) prior to HSCT. Overall mortality rate was significantly higher in the CMV positive group (103/258, 39.9%), as compared to the CMV negative group (152/777, 19.6%) (p value = 0.0001). CMV was the direct cause of death in 13/1035 children (1.2%). GvHD as a cause of death was found to be significantly higher among those with CMV (n = 32) as compared to those without CMV (n = 14) (35.6 versus 9%, p value = 0.0001). The incidence of CMV reactivation was noted in 25% of HSCT recipients, and predominantly in haploidentical HSCTs. CMV reactivation was shown to significantly impact all-cause mortality and there was a significantly increased risk of mortality due to GvHD among those with CMV reactivation.
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7.
Diagnostic performance of a multiplexed gastrointestinal PCR panel for identifying diarrheal pathogens in children undergoing hematopoietic stem cell transplant
Tao, Y., Luo, C. J., Zhang, B. H., Shen, X. Y., Zhao, R. K., Ma, B. Y., Shen, N., Luo, C. Y., Wang, J. M., Xia, Y. J., et al
World journal of pediatrics : WJP. 2024
Abstract
BACKGROUND Diarrhea is a common complication of hematopoietic stem cell transplantation (HSCT) and is associated with substantial morbidity, but its etiology is often unknown. Etiologies of diarrhea in this population include infectious causes, chemotherapy- or medication-induced mucosal injury and graft-versus-host disease (GVHD). Distinguishing these potential causes of diarrhea is challenging since diarrheal symptoms are often multifactorial, and the etiologies often overlap in transplant patients. The objectives of this study were to evaluate whether the FilmArray gastrointestinal (GI) panel would increase diagnostic yield and the degree to which pre-transplantation colonization predicts post-transplantation infection. METHODS From November 2019 to February 2021, a total of 158 patients undergoing HSCT were prospectively included in the study. Stool specimens were obtained from all HSCT recipients prior to conditioning therapy, 28 ± 7 days after transplantation and at any new episode of diarrhea. All stool samples were tested by the FilmArray GI panel and other clinical microbiological assays. RESULTS The primary cause of post-transplantation diarrhea was infection (57/84, 67.86%), followed by medication (38/84, 45.24%) and GVHD (21/84, 25.00%). Ninety-five of 158 patients were colonized with at least one gastrointestinal pathogen before conditioning therapy, and the incidence of infectious diarrhea was significantly higher in colonized patients (47/95, 49.47%) than in non-colonized patients (10/63, 15.87%) (P < 0.001). Fourteen of 19 (73.68%) patients who were initially colonized with norovirus pre-transplantation developed a post-transplantation norovirus infection. Twenty-four of 62 (38.71%) patients colonized with Clostridium difficile developed a diarrheal infection. In addition, FilmArray GI panel testing improved the diagnostic yield by almost twofold in our study (55/92, 59.78% vs. 30/92, 32.61%). CONCLUSIONS Our data show that more than half of pediatric patients who were admitted for HSCT were colonized with various gastrointestinal pathogens, and more than one-third of these pathogens were associated with post-transplantation diarrhea. In addition, the FilmArray GI panel can increase the detection rate of diarrheal pathogens in pediatric HSCT patients, but the panel needs to be optimized for pathogen species, and further studies assessing its clinical impact and cost-effectiveness in this specific patient population are also needed.
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8.
Gaining Consensus Around Patient Risk Groups and Prognostic Profiles to Guide CMV Management Among Patients With Allogeneic Hematopoietic Stem Cell Transplant: Insights From a Delphi Panel With Hematopoietic Stem Cell Transplant Experts
Graf, M., Tuly, R., Pednekar, P., Wang, C., Batt, K.
Transplantation proceedings. 2024
Abstract
INTRODUCTION This study aimed to characterize patient risk groups and prognostic profiles to optimize clinical decision-making and guide appropriate medical cytomegalovirus (CMV) management among patients with allogeneic hematopoietic stem cell transplant (HSCT). METHODS Between 8/2021 and 2/2022, a 3-round modified Delphi study was conducted to generate consensus among 10 international experts in HSCT and infectious diseases. Experts were asked about treatment and prognoses for patients in 7 distinct clinical scenarios. Furthermore, experts were asked to risk-stratify patients by pre-/post-transplant characteristics. Consensus around opting for/against a treatment was observed if ≥75% or <25% of experts reported ≥50% likelihood to recommend or if treatments were ranked inside/outside the top 2 options and ≥75% of experts were within 1 SD of mean ranks. RESULTS Experts agreed on several unmet needs in CMV disease management post-HSCT, particularly avoidance of treatment-limiting toxicities with conventional CMV therapy and the emergence of both refractory and drug-resistant treatment failures. Experts considered CMV viral load, resistance profile, and route of administration as critical to treatment selection. For newer CMV therapeutic options, experts listed a lack of long-term use data, concerns over potential resistance, high cost, and limited availability as challenges restricting adoption and successful patient management. CONCLUSIONS Experts achieved consensus around patient risk stratifications and factors influencing therapeutic options. Recommendations emerging from this Delphi study may support practicing physicians when confronted with challenging CMV scenarios in patients with HSCT.
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9.
Early T-cell reconstitution predicts risk of EBV reactivation after allogeneic hematopoietic stem cell transplantation
Huang, J., Pan, Z., Wang, L., Zhang, Z., Huang, J., Jiang, C., Cai, G., Yin, T.
Clinical and experimental medicine. 2024;24(1):22
Abstract
The quality of immune reconstitution (IR) is crucial for the outcome of patients who received allogeneic hematopoietic stem cell transplantation (allo-HSCT), and is closely connected with infection, relapse and graft-versus-host disease (GvHD) which are the most important causes for transplantation failure. However, the IR pattern in the early stage after allo-HSCT, particularly haploidentical (HID) HSCT, remains unclear. In this retrospective study, we examined the T cell reconstitution of patients within the initial 30 days (n = 173) and 100 days (n = 122) after allo-HSCT with myeloablative condition (MAC), of which > 70% were HID HSCT, to assess the influence of IR on the transplant outcomes. By comparing 78 patients with good IR (GIR) to 44 patients with poor IR (PIR), we observed that GIR was associated with lower risk for Epstein-Barr virus (EBV) reactivation and cytomegalovirus (CMV) reactivation, but had no significant impacts on the survival outcomes (i.e., overall survival, event-free survival) and cumulative incidences of GvHD. Importantly, we found lymphocyte reconstitution pattern at day 30 after allo-HSCT would be a surrogate for IR evaluated at day 100. In the Cox proportional hazard model, early reconstitution of CD4(+), CD4(+)CD25(+), CD4(+)CD45RO(+), CD4(+)CD25(+)CD27(low), and CD8(+) T cells at day 30 was reversely correlated with risk of EBV reactivation. Finally, we constructed a predictive model for EBV reactivation with CD8(+) and CD4(+)CD45RO(+) T cell proportions of the training cohort (n = 102), which was validated with a validation cohort (n = 37). In summary, our study found that the quality of IR at day 30 had a predictive value for the risk of EBV reactivation, and might provide guidance for close monitoring for EBV reactivation.
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10.
The clinical value of anal swabs for microbial detection in allogeneic haematopoietic stem cell transplantation
Gao, J., Lin, D., Hou, C., Shen, Y., Li, Y., Wu, D., Xu, Y.
Transplantation and cellular therapy. 2023
Abstract
BACKGROUND The intestinal microbiota plays critical roles in allogeneic haematopoietic stem cell transplantation (allo-HSCT). Rapid and effective microbial detection methods have important guiding value for the selection of intervention strategies for transplant patients. We evaluate the application of anal swab test before transplantation in allo-HSCT patients. STUDY DESIGN A total of 120 allo-HSCT patients who underwent anal swab testing before allo-HSCT were retrospectively analysed and divided into sterile (aseptic growth-negative), G+ (gram-positive bacterial colonization) and G- (gram-negative bacterial colonization) groups. RESULTS 16S rRNA sequencing showed that gram-negative bacteria predominated in the G- group before and after transplantation. Compared with the sterile group, NK cell percentage was higher and T cell percentage was lower after transplantation in the G- group at one month after transplantation. The percentage of CD4+T and CD4+CD8+ T cells was lower, and the percentage of Treg was higher in the G- group. The plasma levels of pro-inflammatory cytokines (TNF-α, IFN-γ, IL-6, and IL-17A) were lower in the G- group at 2 weeks after transplantation than in the sterile group. The cumulative incidence of grade III-IV aGVHD was lower in the G- group than in the sterile group. Gram-negative bacterial colonization before allo-HSCT was associated with low rates of BSI within 100 days posttransplatation, and CMV reactivation after 100 days to 2 years posttransplatation. Moreover, patients in the G- group had a higher rate of 2-year GRFS compared with patients in the sterile group. CONCLUSIONS The detection results using anal swabs were consistent with the gram-negative or positive bacteria abundance of 16S rRNA sequencing results and associated with immune homeostasis and clinical outcomes after allo-HSCT. Anal swab testing may have potential advantages as a simple and effective method for microbial detection in allo-HSCT.