The effects of antibiotic exposures on the gut resistome during hematopoietic cell transplantation in children.

Antibiotic resistance is a global threat driven primarily by antibiotic use. We evaluated the effects of antibiotic exposures on the gut microbiomes and resistomes of children at high risk of colonization by antibiotic-resistant bacteria. We performed shotgun metagenomic sequencing of 691 serially collected fecal samples from 80 children (<18 years) undergoing hematopoietic cell transplantation. We evaluated the effects of aerobic (cefepime, vancomycin, fluoroquinolones, aminoglycosides, macrolides, and trimethoprim-sulfamethoxazole) and anaerobic (piperacillin-tazobactam, carbapenems, metronidazole, and clindamycin) antibiotic exposures on the diversity and composition of the gut microbiome and resistome. We identified 372 unique antibiotic resistance genes (ARGs); the most frequent ARGs identified encode resistance to tetracyclines (n = 88), beta-lactams (n = 84), and fluoroquinolones (n = 79). Both aerobic and anaerobic antibiotic exposures were associated with a decrease in the number of bacterial species (aerobic, ß = 0.71, 95% CI: 0.64, 0.79; anaerobic, ß = 0.66, 95% CI: 0.53, 0.82) and the number of unique ARGs (aerobic, ß = 0.81, 95% CI: 0.74, 0.90; anaerobic, ß = 0.73, 95% CI: 0.61, 0.88) within the gut metagenome. However, only antibiotic regimens that included anaerobic activity were associated with an increase in acquisition of new ARGs (anaerobic, ß = 1.50; 95% CI: 1.12, 2.01) and an increase in the relative abundance of ARGs in the gut resistome (anaerobic, ß = 1.62; 95% CI: 1.15, 2.27). Specific antibiotic exposures were associated with distinct changes in the number and abundance of ARGs for individual antibiotic classes. Our findings detail the impact of antibiotics on the gut microbiome and resistome and demonstrate that anaerobic antibiotics are particularly likely to promote acquisition and expansion of antibiotic-resistant bacteria.

Characterization of direct oral anticoagulants use in adult hematopoietic stem cell transplant recipients.

Direct oral anticoagulants (DOACs) for venous thromboembolism (VTE) treatment are of interest in oncology due to ease of administration and lack of need for therapeutic monitoring compared to other anticoagulants. Data supporting their use in patients with hematologic malignancies post-hematopoietic stem cell transplant (HCT) are limited. The purpose of the study is to characterize DOAC use in HCT patients. This multicenter, retrospective cohort analysis included allogeneic and autologous HCT recipients. The primary outcome was major bleeding. Secondary outcomes included clinically relevant non-major bleeding (CRNMB)/minor bleeding and VTE recurrence. Of 126 patients, 91 (72.2%) patients received an autologous HCT, and 35 (27.8%) patients received an allo-HCT. No major bleeding occurred in either transplant recipient groups. In autologous HCT recipients, CRNMB/minor bleeding occurred in four (4.4%) patients and VTE recurrence occurred in one (1.1%) patient. For allogeneic HCT recipients, CRNMB/minor bleeding occurred in five (14.3%) patients and VTE recurrence occurred in two (5.7%) patients. For patients that experienced a CRNMB, five (100%) of the allogeneic HCT and two (50%) of the autologous HCT recipients were thrombocytopenic at the time of bleeding. Only 38.5% of patients who experienced a drug-drug interaction requiring DOAC dose adjustment received the appropriate dose adjustment. DOACs were associated with low rates of recurrent VTE and no major bleeding events, similar to published data on DOAC use in the general cancer patient population. This suggests that DOACs may be safe therapeutic options with proactive management of drug interactions and careful monitoring for bleeding events, especially in the allogeneic HCT population where minor bleeding rates were slightly higher.

Predictors of lenalidomide maintenance duration after autologous stem cell transplant in patients with multiple myeloma.

BACKGROUND: For patients with multiple myeloma (MM) who have undergone autologous stem cell transplant (auto-SCT), the immunomodulatory agent lenalidomide is a first-line option for maintenance therapy. Because longer durations of lenalidomide maintenance are associated with improved survival, identifying strategies to avoid premature cessation of maintenance is an important priority in the post-transplant setting. OBJECTIVES: The primary objective of this analysis was to identify specific clinical predictors of lenalidomide treatment duration that could guide optimal medication management. Key secondary objectives included predictors of intolerable toxicity, rationale for lenalidomide dose reduction/discontinuation, and characterization of dose adjustments. STUDY DESIGN: This retrospective, multi-center cohort study included adults with MM who underwent auto-SCT and initiated maintenance lenalidomide between 01/01/2012 and 02/28/2021. Variables assessed as potential predictors of maintenance duration or intolerable toxicity included age, body mass index (BMI), Eastern Cooperative Oncology Group (ECOG) performance status at time of auto-SCT, renal function, initial lenalidomide dose, use of combination maintenance therapy, and cytogenetic risk category. RESULTS: Among 299 patients included, the median age at time of auto-SCT was 62 years (range 30-77). The majority of patients had standard-risk cytogenetics (64%) and an ECOG performance status of 0 or 1 (72%). In the overall population, the median duration of maintenance was 1.3 years (range 0.3-8.6 years). The median initial dose of lenalidomide was 10 mg daily (range 2.5-25 mg). During the study period, 35% of patients had a dose reduction due to toxicity, 21% stopped lenalidomide due to disease progression, and 19% stopped due to toxicity. Multivariate linear regression analyses did not identify any significant predictors of lenalidomide duration or discontinuation due to intolerable toxicity. The most frequently reported toxicities leading to discontinuation were cytopenias, rash, and fatigue. CONCLUSION: This analysis did not identify any significant risk factors to predict the duration of lenalidomide maintenance or discontinuation for toxicity following auto-SCT in patients with MM. While limited by the retrospective design and relatively small sample size, our findings suggest that a priori lenalidomide dose reductions based on patient co-morbidities or performance status may not substantially affect the duration of lenalidomide maintenance.

Comparing Consumer-Directed Hospital Rankings With STS Adult Cardiac Surgery Database Outcomes.

BACKGROUND: Public interest in stratifying hospital performance has led to the proliferation of commercial, consumer-oriented hospital rankings. In cardiac surgery, little is known about how these rankings correlate with clinical registry quality ratings. METHODS: The Society of Thoracic Surgeons (STS) Adult Cardiac Surgery Database was queried for isolated coronary artery bypass grafting or coronary artery bypass grafting/valve patients at hospitals among the top 100 U.S. News & World Report (USNWR) Cardiology & Heart Surgery rankings from 2016 to 2020. Hospitals were grouped into deciles by risk-adjusted observed/expected (O/E) ratios for morbidity and mortality using the STS 2018 risk models. Agreement between STS Adult Cardiac Surgery Database and USNWR ranked deciles was calculated by Bowker symmetry test. The association between each center's annual change in STS O/E ratio and change in USNWR ranking was modeled in repeated measures regression analysis. RESULTS: Inclusion criteria were met by 524 393 patients from 149 hospitals that ranked in USNWR top 100 at least once during the study period. There was no agreement between USNWR ranking and STS major morbidity and mortality O/E ratio (P > .50 for all years). Analysis of patients undergoing surgery at the 65 hospitals that were consistently ranked in the top 100 during the study period demonstrated no association between annual change in hospital ranking and change in O/E ratio (P all > .3). CONCLUSIONS: There was no agreement between annual USNWR hospital ranking and corresponding risk-adjusted STS morbidity or mortality. Furthermore, annual changes in USNWR rankings could not be accounted for using clinical outcomes. These findings suggest that factors unrelated to key surgical outcomes may be driving consumer-directed rankings.

Hospital Readmissions Among Veterans Within 90 Days of Discharge Following Initial Hospitalization for COVID-19.

INTRODUCTION: Some patients experience ongoing sequelae after discharge, including rehospitalization; therefore, outcomes following COVID-19 hospitalization are of continued interest. We examined readmissions within 90 days of hospital discharge for veterans hospitalized with COVID-19 during the first 10 months of the pandemic in the US. METHODS: Veterans hospitalized with COVID-19 at a Veterans Health Administration (VA) hospital from March 1, 2020, through December 31, 2020 were followed for 90 days after discharge to determine readmission rates. RESULTS: Of 20,414 veterans hospitalized with COVID-19 during this time period, 13% (n = 2,643) died in the hospital. Among survivors (n = 17,771), 16% (n = 2,764) were readmitted within 90 days of discharge, with a mean time to readmission of 21.6 days (SD = 21.1). Characteristics of the initial COVID-19 hospitalization associated with readmission included length of stay, mechanical ventilator use, higher comorbidity index score, current smoking, urban residence, discharged against medical advice, and hospitalized from September through December 2020 versus March through August 2020 (all P values <.02). Veterans readmitted from September through December 2020 were more often White, lived in a rural or highly rural area, and had shorter initial hospitalizations than veterans hospitalized earlier in the year. CONCLUSION: Approximately 1 of 6 veterans discharged alive following a COVID-19 hospitalization from March 1 through December 31, 2020, were readmitted within 90 days. The longer the hospital stay, the greater the likelihood of readmission. Readmissions also were more likely when the initial admission required mechanical ventilation, or when the veteran had multiple comorbidities, smoked, or lived in an urban area. COVID-19 hospitalizations were shorter from September through December 2020, suggesting that hospital over-capacity may have resulted in earlier discharges and increased readmissions. Efforts to monitor and provide support for patients discharged in high bed-capacity situations may help avoid readmissions.

Outcomes of acute type A aortic dissection during the COVID-19 pandemic: An analysis of the Society of Thoracic Surgeons Database.

PURPOSE: There have been reported reductions of hospital presentation for acute cardiovascular conditions such as myocardial infarction and acute type A aortic dissection (ATAAD) in the United States during the COVID-19 pandemic. This study examined presentation patterns and outcomes of ATAAD in North America immediately before, and during, the COVID-19 pandemic. METHODS: The Society of Thoracic Surgeons Adult Cardiac Surgery Database (STS ACSD) was queried to identify patients presenting with ATAAD in the 12 months pre-pandemic (March 2019-February 2020), and during the early pandemic (March through June 2020). Demographics and operative characteristics were compared using χ² test and Wilcoxon Rank-sum test. The median annual case volume designated low-volume centers versus high-volume centers (>10 cases per month). Step-wise variable selection was used to create a risk set used for adjustment of all multivariable models. RESULTS: There were 5480 patients identified: 4346 pre-pandemic and 1134 during pandemic. There was significantly lower volume of median cases per month during the COVID-19 pandemic period (286 interquartile range [IQR]: 256-306 vs. 372 IQR: 291-433,p = .0152). In historically low-volume centers (<10 cases per year), there was no difference in volume between the two periods (142 IQR: 133-166 vs. 177 IQR: 139-209, p = NS). In high-volume centers, there was a decline during the pandemic (140 IQR: 123-148 vs. 212 IQR: 148-224, p = .0052). There was no difference in overall hospital-to-hospital transfers during the two time periods (54% of cases pre-pandemic, 55% during). Patient demographics, operative characteristics, malperfusion rates, and cardiac risk factors were similar between the two time periods. There was no difference in unadjusted operative mortality (19.01% pre-pandemic vs. 18.83% during, p = .9) nor major morbidity (52.42% pre-pandemic vs. 51.24% during, p = .5). Risk-adjusted multivariable models showed no difference in either operative mortality nor major morbidity between time periods. CONCLUSIONS: For patients presenting to the hospital with ATAAD during the first surge of the pandemic, operative outcomes were similar to pre-pandemic despite a 30% reduction in volume. Out-of-hospital mortality from ATAAD during the pandemic remains unknown. Further understanding these findings will inform management of ATAAD during future pandemics.

Epstein-Barr Virus DNAemia and post-transplant lymphoproliferative disorder in pediatric solid organ transplant recipients.

BACKGROUND: Pediatric solid organ transplant (SOT) recipients commonly have Epstein-Barr virus (EBV) DNAemia and are at risk of developing post-transplant lymphoproliferative disorder (PTLD). EBV DNAemia has not been analyzed on a continuous scale in this population. METHODS: All children ≤ 18 years of age who underwent SOT at a single center between January 1, 2007 and July 31, 2018 were included in this retrospective study. Transplant episodes in which PTLD occurred were compared to transplant episodes without PTLD. Multivariable logistic regression was used to identify factors associated with the development of EBV DNAemia and maximum height of EBV DNAemia. A Cox proportional hazards model was used to calculate hazard ratios for time to PTLD. RESULTS: Of 275 total transplant recipients and 294 transplant episodes, there were 14 episodes of PTLD. Intestinal and multivisceral transplant were strongly associated with PTLD (p = 0.002). Risk factors for the development of EBV DNAemia include donor and recipient positive EBV serologies (p = 0.001) and older age (p = 0.001). Maximum level of EBV DNAemia was significantly associated with development of PTLD (p<0.0001). Every one log (log10) increase in the maximum level of EBV DNAemia was associated with a more than doubling of the hazard on developing PTLD (HR: 2.18, 95% CI 1.19-3.99). CONCLUSIONS: Transplant type was strongly associated with development of PTLD in pediatric SOT recipients. EBV serologies and age were associated with the development of EBV DNAemia and height of DNAemia. High levels of EBV DNAemia were strongly associated with an increased hazard for PTLD.

Characterisation of infections in patients with acute myeloid leukaemia receiving venetoclax and a hypomethylating agent.

We investigated the incidence of invasive fungal infections (IFIs) and other infectious complications in patients receiving venetoclax and hypomethylating agent therapy for acute myeloid leukaemia (AML). This retrospective, multicentre cohort study included adult patients with AML who received at least one cycle of venetoclax and either azacitidine or decitabine between January 2016 and August 2020. The primary outcome was the incidence of probable or confirmed IFI. Secondary outcomes included antifungal prophylaxis prescribing patterns, incidence of bacterial infections, and incidence of neutropenic fever hospital admissions. Among 235 patients, the incidence of probable or confirmed IFI was 5.1%. IFI incidence did not differ significantly according to age, antifungal prophylaxis use, or disease status. In the subgroup of patients with probable or confirmed IFIs, six (50%) were receiving antifungal prophylaxis at the time of infection. The overall incidence of developing at least one bacterial infection was 33.6% and 127 (54%) patients had at least one hospital admission for febrile neutropenia. This study demonstrated an overall low risk of developing probable or confirmed IFI as well as a notable percentage of documented bacterial infections and hospital admissions due to neutropenic fever.

Risk Factors for CMV Viremia and Treatment-Associated Adverse Events Among Pediatric Hematopoietic Stem Cell Transplant Recipients.

BACKGROUND: Cytomegalovirus (CMV) causes substantial morbidity and mortality after hematopoietic stem cell transplantation (HSCT). There are limited data on risk factors for CMV viremia and the safety of antiviral medications used to treat CMV in children. METHODS: We conducted a single-center retrospective study of children who underwent HSCT between 2000 and 2016. We used log-logistic regression to evaluate associations between clinical characteristics and CMV-free survival at 100 days after HSCT. We compared the incidences of laboratory-defined adverse events (AEs) during treatment with ganciclovir and foscarnet. RESULTS: Among 969 children, the median (interquartile range) age was 6.5 (3.1-11.5) years, and 80% underwent allogeneic HSCT. Two hundred forty-four (25%) children developed CMV viremia. Older age (odds ratio [OR], 0.95; 95% CI, 0.92-0.98), male sex (OR, 0.71; 95% CI, 0.51-0.99), non-Black, non-White race (OR, 0.56; 95% CI, 0.36-0.87), umbilical cord blood donor source (OR, 0.28; 95% CI, 0.08-0.97), and CMV seropositivity (R-/D+: OR, 0.17; 95% CI, 0.07-0.41; R+/D-: OR, 0.14; 95% CI, 0.09-0.21; R+/D+: OR, 0.08; 95% CI, 0.04-0.15) were associated with lower odds of 100-day CMV-free survival. Compared with foscarnet, ganciclovir was associated with lower incidences of thrombocytopenia (incidence rate ratio [IRR], 0.38; 95% CI, 0.15-0.97), electrolyte AEs (IRR, 0.42; 95% CI, 0.24-0.75), endocrine AEs (IRR, 0.52; 95% CI, 0.34-0.79), and renal AEs (IRR, 0.36; 95% CI, 0.19-0.65). CONCLUSIONS: CMV viremia occurred commonly among children after HSCT, and ganciclovir and foscarnet were associated with distinct toxicity profiles among children with CMV infection. These findings should be considered when developing CMV prevention and treatment strategies for children after HSCT.

Complete response following treatment of plasma cell leukemia with venetoclax and dexamethasone: A case report.

INTRODUCTION: Plasma cell leukemia (PCL) is a rare but aggressive variant of multiple myeloma (MM) with a poor prognosis. Due to the limited number of prospective clinical trials studying PCL, treatment options are often extrapolated from data available for the treatment of MM. Venetoclax has recently demonstrated antimyeloma activity in patients with relapsed/refractory MM carrying the t(11;14) translocation. However, few cases have reported the analogous efficacy of venetoclax in PCL. CASE REPORT: A 64-year-old Caucasian male developed relapsed PCL despite treatment with hyperCD (hyperfractionated cyclophosphamide and dexamethasone) and Dara-KRd (daratumumab, carfilzomib, lenalidomide, dexamethasone). Due to the refractory nature of his disease and the presence of a t(11:14) translocation, the patient was subsequently initiated on venetoclax 400 mg daily and dexamethasone 4 mg once weekly. MANAGEMENT AND OUTCOME: The patient achieved a complete response by International Myeloma Working Group criteria three months after initiating venetoclax-dexamethasone, including a repeat bone marrow biopsy that showed no abnormal plasma cells. He successfully underwent consolidation with melphalan-based autologous stem cell transplantation. He remains disease-free 9 months after venetoclax initiation. DISCUSSION: Combination all-oral therapy with venetoclax and dexamethasone can induce deep hematologic responses in patients with relapsed/refractory PCL carrying the t(11;14) translocation.

Evaluation of subcutaneous daratumumab injections in the ambulatory care setting.

INTRODUCTION: Subcutaneous daratumumab is non-inferior to intravenous daratumumab for the treatment of multiple myeloma and significantly reduced incidence of systemic reactions. However, manufacturer for subcutaneous daratumumab has not provided guidance regarding optimal methods for monitoring for hypersensitivity reactions following subcutaneous daratumumab administration. METHODS: A retrospective analysis was performed in two cohorts of patients who received at least two doses of subcutaneous daratumumab for the treatment of plasma cell disorders: patients with previous exposure to intravenous daratumumab (dara-exposed) and patients without history of intravenous daratumumab (dara-naïve). The primary outcome was incidence of systemic and injection-site reactions following first dose of subcutaneous daratumumab. Secondary analysis included time to systemic and injection-site reactions, grading of adverse reaction, and incidence of second systemic reaction. RESULTS: Thirty-one patients were dara-naïve and 49 patients were dara-exposed. Differences in incidence of systemic (dara-naïve: 9.7% vs dara-exposed: 6.1%, p = 0.67) and injection-site reactions (dara-naïve: 12.9% vs dara-exposed: 14.3%, p = 0.99) did not reach statistical significance. Difference in median time to systemic reaction (dara-naïve: 3 h vs dara-exposed: 12 h, p = 0.18) was clinically important but did not reach statistical significance. Median time to injection-site reactions (dara-naïve: 6 h vs dara-exposed: 24 h, p = 0.03) was shorter in the dara-naïve cohort. No clinically meaningful difference was observed for incidence of second systemic reaction. CONCLUSION: Most reactions were mild and did not require medical intervention. Following first subcutaneous daratumumab dose, monitoring for 3 h for dara-naïve patients and no monitoring time for dara-exposed patients for hypersensitivity reactions may be a safe and reasonable practice.

Phylogenomic Analysis of Velvet Worms (Onychophora) Uncovers an Evolutionary Radiation in the Neotropics.

Onychophora ("velvet worms") are charismatic soil invertebrates known for their status as a "living fossil," their phylogenetic affiliation to arthropods, and their distinctive biogeographic patterns. However, several aspects of their internal phylogenetic relationships remain unresolved, limiting our understanding of the group's evolutionary history, particularly with regard to changes in reproductive mode and dispersal ability. To address these gaps, we used RNA sequencing and phylogenomic analysis of transcriptomes to reconstruct the evolutionary relationships and infer divergence times within the phylum. We recovered a fully resolved and well-supported phylogeny for the circum-Antarctic family Peripatopsidae, which retains signals of Gondwanan vicariance and showcases the evolutionary lability of reproductive mode in the family. Within the Neotropical clade of Peripatidae, though, we found that amino acid-translated sequence data masked nearly all phylogenetic signal, resulting in highly unstable and poorly supported relationships. Analyses using nucleotide sequence data were able to resolve many more relationships, though we still saw discordant phylogenetic signal between genes, probably indicative of a rapid, mid-Cretaceous radiation in the group. Finally, we hypothesize that the unique reproductive mode of placentotrophic viviparity found in all Neotropical peripatids may have facilitated the multiple inferred instances of over-water dispersal and establishment on oceanic islands.

Impact of Polypharmacy Prior to Allogeneic Hematopoietic Stem Cell Transplantation in Older Adults.

Polypharmacy is common in older adults with cancer, but there is little evidence evaluating the impact of polypharmacy and other medication hazards on allogeneic hematopoietic cell transplantation (alloHCT) outcomes. A small number of prior studies have evaluated the impact of potentially inappropriate medication (PIM) use in the setting of alloHCT, with mixed results. We evaluated the effects of pre-alloHCT polypharmacy, PIM use, and drug-drug interactions (DDIs) on post-alloHCT outcomes, including overall survival (OS), progression-free survival (PFS), non-relapse mortality (NRM), hospital length of stay (LOS), number of non-hematologic grade ≥3 adverse events (AEs) within 100 days after alloHCT, and number of readmissions within the first 100 days after alloHCT. The study population was a single-center prospective cohort of 148 patients ≥ 50 years of age. Pre-alloHCT medication lists were retrospectively collected from the electronic medical record, including both scheduled and as-needed medications. PIMs were defined by a modified 2019 American Geriatrics Society Beers Criteria. DDIs were analyzed using Lexi-Interact. Polypharmacy was common in this population; the median number of medications was seven (range, 0 to 23). Fifty-two patients (35%) were prescribed nine or more medications, and 73 patients (49%) had at least one PIM prescribed. The median number of DDIs was three (range, 0 to 31), and the most common severity was major (48%). After adjusting for age and Hematopoietic Cell Transplant Comorbidity Index (HCTCI), both the number of all medications and number of scheduled medications were associated with inferior OS, with hazard ratios (HRs) of 1.07 (95% confidence interval [CI], 1.01 to 1.12; P = .02) and 1.08 (95% CI, 1.00 to 1.15; P = .04), respectively. Receipt of nine or more scheduled medications was associated with inferior OS (HR, 1.92; 95% CI, 1.11 to 3.32; P = .02). The number of PIMs was also significantly associated with OS (HR, 1.24; 95% CI, 1.00 to 1.54, P = .05). After adjusting for age, HCTCI, and total number of medications, a greater number of DDIs were significantly associated with longer hospital length of stay (difference, 0.74 days; 95% CI, 0.09 to 1.40, P = .03). In adjusted analyses, there were no significant polypharmacy-related predictors of NRM, LOS, or non-hematologic grade ≥3 AEs. These data demonstrate the utility of pre-alloHCT polypharmacy, PIM use, and DDIs as important prognostic factors and support routine pre-alloHCT medication review by physicians and pharmacists with a goal of appropriate de-prescribing where possible.

Risks and outcomes of adenovirus disease in pediatric hematopoietic stem cell transplant recipients-Comparison of current antiviral treatment options.

BACKGROUND: Adenovirus disease (ADVd) is a significant burden in pediatric hematopoietic stem cell transplant (HSCT) recipients. However, current knowledge of risk factors associated with poor clinical outcome and the effectiveness of antiviral therapy are not well understood. This study determined the relationship between transplant characteristics and risk of ADVd and also compared time to resolution of disease between pediatric patients who did and did not receive antiviral therapy. METHODS: We conducted a retrospective, single-center cohort study of pediatric patients undergoing HSCT at Duke University (2005-2016). Cases of ADVd were defined a priori using a classification tool. Cox proportional hazards (CPH) regression models were used to compare the hazard of ADVd between HSCT recipients differing by type of transplant and type of conditioning regimen. The hazard of time to resolution of ADVd by antiviral therapy (cidofovir, brincidofovir, both, or neither) was compared. RESULTS: Ninety-three of 830 subjects had ADVd post-HSCT (11.2%). Umbilical cord transplant (UCT) recipients had 2.30 (95% CI 1.57, 6.90, P = .002) higher hazard of developing ADVd compared to non-cord allogeneic transplants, and 6.30 higher (95% CI 2.70, 19.61, P < .001) hazard compared to autologous transplants. Subjects who did not receive antiviral therapy experienced earlier resolution of ADVd compared to subjects who received therapy, even after adjusting for subjects with disseminated disease (HR [95% CI]: 3.75 [1.57, 8.93], P = .003). CONCLUSIONS: Pediatric UCT recipients are at a higher risk for ADVd. Antiviral therapy was not associated with an earlier resolution of ADVd, even in patients with higher disease burden.

Microbiology of Bloodstream Infections in Children After Hematopoietic Stem Cell Transplantation: A Single-Center Experience Over Two Decades (1997-2017).

BACKGROUND: Bloodstream infections (BSIs) occur frequently after hematopoietic stem cell transplantation (HSCT). We examined the microbiology of BSI in pediatric HSCT recipients over a 2-decade period at our institution to inform empirical antimicrobial prescribing and infection prevention strategies. METHODS: We conducted a retrospective cohort study of children (<18 years) who underwent HSCT at Duke University between 1997 and 2015. We used recurrent-event gap-time Cox proportional hazards models to determine the hazards of all-cause and cause-specific BSI according to HSCT year. We compared the median time to BSI by causative organism type and evaluated for temporal trends in the prevalence of antibiotic resistance among causative organisms. RESULTS: A total of 865 BSI occurred in 1311 children, including 412 (48%) Gram-positive bacterial, 196 (23%) Gram-negative bacterial, 56 (6%) fungal, 23 (3%) mycobacterial, and 178 (21%) polymicrobial BSI. The hazard of all BSIs did not change substantially over time during the study period, but the hazard of fungal BSIs declined over time during the study period (P = .04). Most fungal BSIs (82%) occurred in the first 100 days after HSCT, whereas mycobacterial BSIs occurred later after HSCT than BSIs caused by other organisms (P < .0001). The prevalence of vancomycin resistance among BSIs caused by Enterococcus faecium increased during the study period (P = .0007). The risk of 2-year mortality in children was increased with BSI (P = .02), Gram-negative bacterial BSI (P = .02), and fungal BSI (P < .0001). CONCLUSIONS: Despite expanded practices for BSI prevention over the past several decades, the incidence of BSI remains high in pediatric HSCT recipients at our institution. Additional strategies are urgently needed to effectively prevent BSIs in this high-risk population.

Long-term Follow-up of Hematopoietic Stem Cell Transplant Survivors: A Focus on Screening, Monitoring, and Therapeutics.

Annually, ~50,000 patients undergo hematopoietic stem cell transplantation (HCT) worldwide with almost 22,000 of these patients receiving HCT in the United States. HCT is a curative option for a wide range of hematologic malignancies, and advances in transplantation medicine have resulted in an increase in HCT survivors. It is anticipated that the number of HCT survivors will more than double from 242,000 in 2020 to ~500,000 in 2030. Survivors of HCT are at an increased risk of developing late complications due to exposure to chemotherapy and/or radiation in the pre-, peri-, and post-HCT phases and these cumulative exposures have the potential to damage normal tissue. This tissue damage leads to the early onset of chronic health conditions resulting in premature mortality in HCT survivors, who have a 15-year cumulative incidence of severe or life-threatening chronic health conditions exceeding 40%. Due to the significant burden of morbidity in HCT survivors and the delay in the development of long-term complications, this delicate patient population requires life-long monitoring due to the risk for neuropsychological, cardiac, pulmonary, renal, hepatic, ocular, skeletal, cardiac, endocrine, fertility, and sexual health complications, as well as secondary neoplasms. This review will focus on recent advances in screening, monitoring, and therapeutics for late-occurring or long-term complications in HCT survivors.

Anaerobic Antibiotics and the Risk of Graft-versus-Host Disease after Allogeneic Hematopoietic Stem Cell Transplantation.

Certain anaerobic bacteria are important for maintenance of gut barrier integrity and immune tolerance and may influence the risk of graft-versus-host disease (GVHD) after allogeneic hematopoietic stem cell transplantation (HSCT). We conducted a single-center retrospective cohort study of allogeneic HSCT recipients to evaluate associations between receipt of antibiotics with an anaerobic spectrum of activity and GVHD outcomes. We identified 1214 children and adults who developed febrile neutropenia between 7 days before and 28 days after HSCT and compared GVHD risk and mortality among patients who received anaerobic antibiotics (piperacillin-tazobactam or carbapenems; n = 491) to patients who received only antibiotics with minimal activity against anaerobes (aztreonam, cefepime, or ceftazidime; n = 723). We performed metagenomic sequencing of serial fecal samples from 36 pediatric patients to compare the effects of specific antibiotics on the gut metagenome. Receipt of anaerobic antibiotics was associated with higher hazards of acute gut/liver GVHD (hazard ratio [HR], 1.26; 95% confidence interval [CI], 1.03 to 1.54) and acute GVHD mortality (HR, 1.63; 95% CI, 1.08 to 2.46), but not chronic GVHD diagnosis (HR, 1.04; 95% CI: .84 to 1.28) or chronic GVHD mortality (HR, .88; 95% CI, .53 to 1.45). Anaerobic antibiotics resulted in decreased gut bacterial diversity, reduced abundances of Bifidobacteriales and Clostridiales, and loss of bacterial genes encoding butyrate biosynthesis enzymes from the gut metagenome. Acute gut/liver GVHD was preceded by a sharp decline in bacterial butyrate biosynthesis genes with antibiotic treatment. Our findings demonstrate that exposure to anaerobic antibiotics is associated with increased risks of acute gut/liver GVHD and acute GVHD mortality after allogeneic HSCT. Use of piperacillin-tazobactam or carbapenems should be reserved for febrile neutropenia cases in which anaerobic or multidrug-resistant infections are suspected.

Long-term stability of microbiome diversity and composition in fecal samples stored in eNAT medium.

Fecal samples collected for microbiome analyses are typically frozen to avoid postcollection changes in microbial composition. eNAT is a guanidine thiocyanate-based medium that stabilizes microbial DNA and allows safe specimen handling and shipping by inactivating microorganisms. We collected fecal samples (n = 50) from children undergoing hematopoietic stem cell transplantation. We divided samples into three aliquots: (a) stored in RNAlater and immediately transferred to -80°C; (b) stored in eNAT medium and immediately transferred to -80°C; and (c) stored in eNAT medium at ambient temperature (~20°C) for 30 days prior to transfer to -80°C. Mean (standard deviation) Shannon diversity and Chao1 indices in sample aliquots were 2.05 (0.62) and 23.8 (16.6), respectively. Comparing samples frozen immediately in RNAlater to samples frozen immediately in eNAT, there were no differences in Shannon diversity (p = .51), Chao1 richness (p = .66), and overall microbiome composition (p = .99). Comparing eNAT samples frozen immediately to samples stored at ambient temperature, we identified no differences in Shannon diversity (p = .65), Chao1 richness (p = .87), and overall microbiome composition (p = .99). Storage of fecal samples in eNAT at ambient temperature for 30 days did not alter microbiome richness, diversity, or composition. eNAT may be a useful medium for fecal microbiome studies, particularly when cold chain storage is unavailable.

Microbiology and Risk Factors for Hospital-Associated Bloodstream Infections Among Pediatric Hematopoietic Stem Cell Transplant Recipients.

BACKGROUND: Children undergoing hematopoietic stem cell transplantation (HSCT) are at high risk for hospital-associated bloodstream infections (HA-BSIs). This study aimed to describe the incidence, microbiology, and risk factors for HA-BSI in pediatric HSCT recipients. METHODS: We performed a single-center retrospective cohort study of children and adolescents (<18 years of age) who underwent HSCT over a 20-year period (1997-2016). We determined the incidence and case fatality rate of HA-BSI by causative organism. We used multivariable Poisson regression to identify risk factors for HA-BSI. RESULTS: Of 1294 patients, the majority (86%) received an allogeneic HSCT, most commonly with umbilical cord blood (63%). During the initial HSCT hospitalization, 334 HA-BSIs occurred among 261 (20%) patients. These were classified as gram-positive bacterial (46%), gram-negative bacterial (24%), fungal (12%), mycobacterial (<1%), or polymicrobial (19%). During the study period, there was a decline in the cumulative incidence of HA-BSI (P = .021) and, specifically, fungal HA-BSIs (P = .002). In multivariable analyses, older age (incidence rate ratio [IRR], 1.03; 95% confidence interval [CI], 1.01-1.06), umbilical cord blood donor source (vs bone marrow; IRR, 1.69; 95% CI, 1.19-2.40), and nonmyeloablative conditioning (vs myeloablative; IRR, 1.85; 95% CI, 1.21-2.82) were associated with a higher risk of HA-BSIs. The case fatality rate was higher for fungal HA-BSI than other HA-BSI categories (21% vs 6%; P = .002). CONCLUSIONS: Over the past 2 decades, the incidence of HA-BSIs has declined among pediatric HSCT recipients at our institution. Older age, umbilical cord blood donor source, and nonmyeloablative conditioning regimens are independent risk factors for HA-BSI among children undergoing HSCT.