Julie M. Steinbrink’s research while affiliated with Duke University and other places

Background Diagnostic stewardship of blood culture utilization is paramount to mitigate the risks associated with excessive culturing, including increased contamination rates and inappropriate antimicrobial administration. Although blood culture algorithms have been studied previously, there is insufficient data on their application specifically in solid organ transplant recipients. This study aims to retrospectively apply a blood culture algorithm (initially developed for a non-immunocompromised population) to assess its effectiveness in this immunosuppressed population. Figure 1. Algorithm used by clinical providers to determine if blood cultures are appropriate or inappropriate Methods We conducted a retrospective review of adult solid organ transplant recipients with a blood culture event (BCE) occurring between February 2022 to January 2024 at a single academic medical center. A BCE was defined as the collection of at least one blood culture set for a specific clinical indication. During this time a blood culture algorithm (Figure 1) was implemented across 12 units in the hospital. Patient charts were manually reviewed to categorize BCEs as appropriate (the algorithm agreed with obtaining a blood culture), inappropriate (if the algorithm suggested to not draw a blood culture), or lacking documentation. Results Among 824 BCEs recorded in adult solid organ transplant recipients (Figure 2), 669 (81.2%) were deemed appropriate, 118 (14.3%) were inappropriate, and 37 (5.5%) lacked sufficient documentation. Adjudication of 388 BCEs with available data was performed and revealed 350 (90.2%) negative cultures, 25 (6.4%) true positives, and 13 (3.4%) contaminants (Figure 3). Within the subset of inappropriate BCEs (n=118), 113 (95.8%) yielded negative cultures, while 5 (4.2%) were contaminants; no true positives were identified. Conclusion The retrospective application of the blood culture algorithm did not reveal any missed true positive bacteremias in solid organ transplant recipients. Although this study is limited in scope, it provides initial evidence supporting the cautious application of the algorithm in this population. As a next step, we will adjudciate the remaining 436 BCE in the dataset. Further investigation is warranted to validate these findings and optimize diagnostic stewardship strategies for improved patient outcomes. Disclosures Jessica Seidelman, MD, MPH, 3M: Expert Testimony

Immune responses during acute infection often contain canonical elements which are shared across the responses to an array of agents within a given pathogen class (i.e., respiratory viral infection). Identification of these shared, canonical elements across similar infections offers the potential for impacting development of novel diagnostics and therapeutics. In this way, analysis of host gene expression patterns (‘signatures’) in white blood cells has been shown to be useful for determining the etiology of some acute viral and bacterial infections. In order to study conserved immune elements shared across the host response to related pathogens, we performed in vitro human PBMC challenges with common fungal pathogens (Candida albicans, Cryptococcus neoformans and gattii); four strains of influenza virus (Influenza A/Puerto Rico/08/34 [H1N1, PR8], A/Brisbane/59/2007 [H1N1], A/Solomon Islands/3/2006 [H1N1], and A/Wisconsin/67/2005 [H3N2]); and gram-negative (Escherichia coli) and gram-positive (Streptococcus pneumoniae) bacteria. Exposed human cells were then analyzed for differential gene expression utilizing Affymetrix microarrays. Analysis of pathogen exposure of PBMCs revealed strong, conserved gene expression patterns representing these canonical immune response elements to each broad pathogen class. A 41-gene multinomial signature was developed which correctly classified fungal, viral, or bacterial exposure with 94–98% accuracy. Furthermore, a 21-gene signature consisting of a subset of the discriminatory PBMC-derived genes was capable of accurately differentiating human patients with invasive candidiasis, acute viral infection, or bacterial infection (AUC 0.94, 0.83, and 0.96 respectively). These data reinforce the conserved nature of the genomic responses in human peripheral blood cells upon exposure to infectious agents and highlight the potential for in vitro models to augment our ability to develop novel diagnostic classifiers for acute infectious diseases, particularly devastating fungal infections.

Background Belatacept is a costimulatory blocker that can be used to prevent and treat rejection in lung transplant recipients (LuTRs). The epidemiology of infections in belatacept‐treated LuTRs has not been systematically evaluated. Methods We performed a single‐center retrospective study of all adult LuTRs who received belatacept as prevention or treatment of antibody‐mediated rejection (desensitization) or as part of maintenance immunosuppression from January 1, 2011, to June 30, 2022. We assessed the epidemiology of infections that occurred within 12 months following the first belatacept dose. Results Fifty‐two LuTRs received at least one dose of belatacept as either desensitization (n = 32) or maintenance immunosuppression ( n = 20). Among 45 patients who were cytomegalovirus (CMV) donor and/or recipient seropositive, nine (20%) developed CMV infection. Seven (77%) CMV infections occurred despite valganciclovir prophylaxis and four (44%) were associated with antiviral resistance. Three (6%) LuTRs developed Epstein‐Barr virus (EBV) associated post‐transplant lymphoproliferative disorder (PTLD). Twenty‐five (48%) LuTRs developed 43 bacterial infections and five (10%) developed proven or probable invasive fungal disease. Incidence rates of viral, bacterial, and fungal infections were similar between the desensitization and maintenance groups: incidence rate ratios (95% confidence interval) were 0.70 (0.32–1.57), 1.31 (0.70–2.46), and 2.82 (0.31–25.2), respectively. Infection/PTLD prompted belatacept discontinuation in eight (15%) patients. Conclusions In the first year after belatacept initiation, LuTRs commonly developed CMV infections, EBV+ PTLD, and bacterial infections. Multicenter collaborations are needed to better understand infection risks in LuTRs treated with belatacept. image

Background In kidney transplantation, concerns have been raised regarding increased incidence of viral opportunistic infections in hepatitis C virus (HCV) nucleic acid test (NAT)‐negative (‐) recipients who received HCV NAT‐positive (+) donor kidneys, specifically BK polyomavirus (BKPyV), cytomegalovirus (CMV), and Epstein‐Barr virus (EBV). The purpose of this study was to determine the incidence of these three viral opportunistic infections in HCV NAT‐ recipients who have undergone kidney transplantation with HCV NAT+ donor kidneys at our institution. Methods This was an Institutional Review Board‐approved, single‐center, retrospective case‐control study of HCV NAT‐ kidney transplant recipients with HCV NAT+ donors from 2018 to 2021. The primary outcome was the cumulative incidence of viral infections of BKPyV, CMV, and/or EBV within 1 year following kidney transplantation. Results A total of 231 patients were included, 77 in the exposed (donor HCV NAT+) group and 154 in the control (donor HCV NAT‐) group. The adjusted cumulative incidence of viremia within 1 year did not statistically differ between groups (77% exposed group versus 66% for the control group, hazard ratio 1.34, 95% confidence interval 0.95–1.89). In addition, no statistically significant differences were observed for secondary outcomes with the exception of CMV viremia (62% exposed versus 49% control, p = 0.021). However, there were more patients in the exposed group at high risk for CMV viremia based on serostatus (CMV Donor+/Recipient‐, D+/R‐). Conclusion Among patients who received HCV NAT+ donor kidneys, no clear association was observed between exposure to HCV NAT+ donor kidneys and viral infections of BKPyV, CMV, or EBV. image

Background Transplant infectious diseases (TID) is a growing area of expertise within infectious diseases (ID), but TID training is not standardized. Previous surveys of fellows identified opportunities to improve TID education resources but did not explore didactic, clinical, and nonclinical experiences comprehensively. Methods The American Society of Transplantation ID Community of Practice surveyed adult and pediatric fellows in US-based general ID or dedicated TID training programs to explore their didactic exposure, clinical experiences, and non–direct patient care activities in TID. Results A total of 234 fellows initiated the survey, and 195 (83%) (190 general ID and 19 TID fellows, including 125 adult, 76 pediatric, and 8 combined adult-pediatric fellows) completed the entire survey. More than half of the fellows described receiving no formal curricular content on most foundational topics in transplant medicine. Almost all respondents (>90%) had some inpatient TID experience, but for >60% of fellows this was <12 weeks annually. Clinical exposure varied by fellow and patient type—in an average month rotating on an inpatient TID service, more than half of adult fellows had evaluated ≥10 kidney, liver, or hematopoietic stem cell transplant recipients but <10 heart, lung, pancreas, or intestinal recipients; pediatric fellows saw <10 of all patient types. Nearly half (46%) of general ID fellows had not spent any time in the dedicated TID clinic at their program. Few fellows had participated in protocol development, organ selection meetings, or donor evaluations. Conclusions This survey highlights important gaps in TID training. Given the increasing need for TID specialists, updated curricula and educational resources are needed.

Cytomegalovirus (CMV) infection poses a significant threat to solid organ transplant (SOT) recipients and can lead to various complications and adverse outcomes. In an effort to prevent CMV infection, it is common to utilize prophylactic strategies, including antiviral medications such as valganciclovir, especially for high-risk patients. Risk factors for CMV infection in kidney transplant recipients (KTRs) include CMV mismatch between donor and recipient (i.e., donor positive, recipient negative), and intensity of immunosuppression, such as the use of T-cell depleting agents. However, little attention has been given to KTRs with a history of prior SOTs, despite their prolonged exposure to immunosuppressive regimens. The aim of this retrospective single-center study was to investigate the incidence and implications of CMV DNAemia in KTRs with prior SOTs. The study included 97 KTRs with prior SOTs and 154 KTRs with no prior transplants as a control group. In the study group, the most common SOT before the current kidney transplantation (KT), was a previous KT. Patients in the KTR group with prior SOTs were more sensitized than those in the control group [calculated panel-reactive antibody > 30%: 49 (50.5%) vs. 30 (19.45%) patients, p = 0.001]. There was a 39.2% incidence of CMV DNAemia in the previous SOT group compared to 48.7% in the control group [non-significant (NS)]. Patients with prior SOTs demonstrated a shorter post-transplant time to CMV DNAemia [median time 1.6 months (interquartile range, IQR 0.7–5.8) in the KTRs with prior SOTs vs. 2.6 months (IQR 1.5–8.1) in the control group (p = 0.001)]. Although the study highlights the need for tailored prophylaxis strategies and vigilant monitoring in KTRs with prior SOTs, its limitations, such as its retrospective nature and single-center design, call for further multicenter research to establish comprehensive guidelines for managing CMV DNAemia in this unique patient population. Despite these limitations, this study underscores the importance of recognizing the heightened risk of CMV infection or reactivation in KTRs overall and the potential benefits of proactive intervention to mitigate associated morbidity and mortality.