Implantable mechanical circulatory support (MCS), such as left ventricular assist devices (LVADs), can improve survival in patients with end-stage heart failure. While post-implant complications including MCS-specific infections are well recognized, the outcomes of LVAD recipients with bloodstream infection (BSI) prior to device implantation have not been systemically studied. We performed a single center retrospective study of all consecutive persons who received a Heartmate 3 (HM3) LVAD implanted at our institution between 1/1/17-12/31/23. We compared recipients with and without clinically significant BSI in the three months preceding device implantation. For these two groups, we also compared demographics, clinical characteristics, and outcomes, including post-implant BSI and one-year survival. Over the seven-year period, 498 patients received a HM3, of whom 31 (6%) had a pre-implant BSI (Table 1). The median time from pre-implant BSI to LVAD surgery was 13 days (interquartile range 6-18). The most common pathogens were Gram-positive organisms (22; 71%; Figure 1). Patients with pre-implant BSI were younger (p=.007), had lower Elixhauser co-morbidity indices (p=.004), and were in hospital longer immediately prior to LVAD surgery (p< .001) compared to patients without pre-implant BSI. Cumulative incidence of one-year post-implant BSI was similar in those with and without pre-implant BSI (16% v. 13%; p=.596). Of 31 patients with pre-implant BSI, 11 (35%) developed post-implant MCS-specific infection in the first year (n=9 percutaneous lead infections, n=1 device-specific BSI, n=1 infection of external surfaces of implant). Only one (3%) MCS-specific infection was attributed to the same pathogen (S. aureus) isolated in blood culture prior to implant. Patients with pre-implant BSI had longer index hospitalizations after LVAD implantation (47 v. 29 days; p< .001) but similar one-year survival compared to patients without pre-implant BSI (84% v. 81%; p=.707; Figure 2). Pre-implant BSI in LVAD recipients was not associated with post-implant BSI. One-year survival was similar between LVAD recipients with and without pre-implant BSI. The risk factors, management, and outcomes of pre-implant BSI in LVAD recipients warrant further study. Madeleine R. Heldman, MD, MS, Karius, Inc: Advisor/Consultant Cameron Wolfe, MBBS, Brio-VAD: Advisor/Consultant

Background:Cytomegalovirus (CMV) is a major cause of morbidity following solid organ transplantation, with thoracic organ transplant recipients (TOTRs) representing one of the highest risk groups. Despite this elevated risk, TOTRs are under-represented in clinical research, and current management strategies are largely extrapolated from other transplant populations. Methods:This review synthesizes evidence on CMV epidemiology, clinical outcomes, prevention, and treatment in TOTRs. Key content:Despite the success of antiviral prophylaxis and pre-emptive monitoring strategies in reducing CMV-related complications in this population, late-onset infection and antiviral resistance remain major clinical challenges. We explore the potential role of CMV in chronic rejection, evaluate the utility of CMV cell-mediated immune monitoring, and review the clinical experience with novel antivirals in TOTRs. By identifying key evidence gaps and outlining priorities for future research, this review aims to support the development of targeted and more effective CMV management strategies in this high-risk population.

Solid organ transplant (SOT) recipients frequently undergo cytomegalovirus (CMV) PCR testing throughout their post-transplant course. While CMV infections are common early (< 2 years) after SOT, the prevalence of CMV infections beyond 2 years has not been reported.Figure 1:CMV PCR testing and CMV DNAemia beyond two years after transplant in solid organ transplant recipients who survived to two yearsTable 1:Solid organ transplant recipients who underwent CMV PCR testing at least once beyond two years after transplanta) Chi squared and Fisher exact tests were used for categorical variables and the Mann-Whitney U test was used for continuous variables.b) Heart includes 3 heart-liver recipients and 21 heart-kidney recipients. Kidney includes 61 kidney-pancreas recipients. Liver includes 54 liver-kidney recipients. Intestine includes 4 intestine-liver-pancreas recipients. We performed a single center retrospective study to determine the period prevalence of CMV PCR testing, CMV DNAemia, and CMV disease beyond 2 years after non-lung SOT. All non-lung, adult SOT recipients (SOTR) who underwent their first SOT between 2/24/14-8/1/22 and who survived through 2 years were included. Patients were followed until death, re-transplant, or 8/1/24 (whichever came first). CMV DNAemia was defined as any plasma CMV load ≥ 450 IU/mL, which was a common threshold to initiate preemptive CMV therapy at our institution. CMV PCRs were performed for evaluation of symptoms of CMV disease or as asymptomatic screening at clinician discretion. Patients did not receive CMV prophylaxis beyond 6 months, except for the 30-days following treatment with lymphodepleting antibodies for rejection.Figure 2:Solid organ transplant recipients with CMV infections beyond two years after transplanta) All cases of CMV disease in D+R- and D-R- consisted of CMV syndrome.b ) This seropositive recipient (R+) was an intestine-liver-pancreas recipient who developed proven CMV enteritis involving the small bowel allograft within two weeks after starting corticosteroids for treatment of rejection.c ) Patients were considered to have received high-dose steroids if they had received ≥ 40 mg/day of prednisone (or equivalent) for at least 7 days within the 30 days before the first occurrence of CMV ≥ 450 IU/mL beyond the 2-year post-transplant date.d) Two seropositive (R+) kidney recipients with asymptomatic CMV DNAemia who received high-dose steroids also received anti-thymocyte globulin within the previous 30 days. Both were taking valganciclovir prophylaxis that was underdosed for renal function at the time of initial CMV DNAemia. No other patients with CMV DNAemia received lymphodepleting antibodies within 30 days prior to their first CMV viral load ≥ 450 IU/mL.e) One case of CMV disease (CMV syndrome) in a D-R- kidney recipient was likely due to community acquired CMV infection Of 2261 SOTR who survived to 2 years after their first SOT, 1695 (75%) underwent CMV PCR testing at least once in the period beyond 2 years, with a mean of 8 CMV PCRs per tested patient (range 1-85) during a mean follow-up time of 2.5 years (range 0.1-8.40) beyond the 2-year mark. CMV DNAemia occurred in 36/1695 tested patients (2.1%, Figure 1). Heart transplant and CMV donor positive/recipient negative (D+R-) status were associated with DNAemia (Table 1). Nine of 15 (60%) CMV seropositive (R+) SOTR with DNAemia received high-dose steroids within 30 days of DNAemia onset compared to 1/20 (5%) D+R- SOTR with DNAemia (Fisher exact p < 0.001). CMV disease occurred in 7 tested patients (0.4%), including five D+R- SOTR without prior CMV infection, one R+ patient who received recent high-dose steroids for rejection, and one CMV D-R- patient with primary, community-acquired infection (Figure 2). CMV infections were rare beyond 2 years after non-lung SOT. Late CMV disease occurred in a small number of CMV seronegative SOTR without prior CMV infection and one CMV seropositive SOTR recently treated with high-dose steroids. However, CMV PCR testing beyond the 2-year mark likely has low diagnostic yield for most non-lung SOTR. Madeleine R. Heldman, MD, MS, Karius, Inc: Advisor/Consultant Jennifer Saullo, MD, Pharm D, RMEI Medical Education: Honoraria|UpToDate: Royalties Julie M. Steinbrink, MD, MHS, Biomeme: patents for gene expression classifiers of fungal infection|McGraw Hill Publishing: royalties

CMV cell-mediated immunity (CMV-CMI) testing has emerged as a promising tool to refine CMV risk stratification and inform prevention strategies in transplant recipients, while recent data assess its role in novel cellular therapies. By identifying patients with robust CMV-specific immune responses, these assays can reduce unnecessary antiviral exposure and support individualized decisions on prophylaxis and preemptive therapy. The strongest evidence comes from the solid organ transplant (SOT) setting, where immune-guided strategies can safely shorten prophylaxis duration, particularly in kidney and lung transplantation. In allogeneic hematopoietic cell transplant (HCT) recipients, CMV-CMI could also guide prophylaxis discontinuation and post-prophylaxis surveillance, although data remain more limited and its added value beyond established clinical markers unclear. In chimeric antigen receptor (CAR)-T-cell therapy recipients, CMV-CMI reaches a nadir at Week 2 post-infusion and recovers by Week 4, defining a window of increased vulnerability during which most CMV reactivation occurs. Assessment at this timepoint may help identify high-risk patients; however, the clinical impact of CMV reactivation, and as a result the need for preventive strategies, remain unclear in this setting. Importantly, the major strength of CMV-CMI lies in its consistently high negative predictive value of robust T-cell responses, while its ability to pinpoint highest-risk patients remains limited. Its widespread use is hindered by assay discordance, limited geographic access, and unproven cost-effectiveness. Despite these limitations, CMV-CMI remains the best-studied strategy for individualized CMV management; further standardization and prospective validation are needed to define its role in increasingly complex immunocompromised populations.

Toxoplasma gondii infection poses a significant risk for donor seropositive recipient seronegative heart transplant patients without prophylaxis. Guidelines remain unclear on the optimal duration of prophylaxis in this population. We present a case of disseminated toxoplasmosis presenting as a subacute diarrheal illness leading to fulminant infection with pulmonary involvement in a 38-year-old woman 6 months after stopping primary chemoprophylaxis.

BackgroundLomentospora prolificans is a rare and often fatal cause of invasive mold disease (IMD), particularly in immunocompromised individuals. Treatment remains difficult due to intrinsic resistance to most antifungals and the challenges of achieving therapeutic drug levels in the central nervous system. Fosmanogepix and olorofim are novel antifungal agents with promising activity against difficult-to-treat molds, including L. prolificans, and show potential for excellent central nervous system penetration.Case SummaryWe report a case of disseminated L. prolificans infection with pulmonary, ocular, and central nervous system involvement in a 73-year-old man following haploidentical hematopoietic cell transplantation for peripheral T-cell lymphoma. Despite early neutrophil engraftment, the absence of graft-versus-host disease, and treatment with fosmanogepix, his infection progressed to fatal fungal meningitis.ConclusionThis case underscores the limitations of relying on in vitro susceptibility results to predict clinical response in the absence of clinical breakpoints, particularly in deep-seated infections where drug penetration may be limited. While prior case reports have described successful outcomes with novel agents, publication bias may overrepresent favorable results. This case supports the urgent need for rigorous evaluation of emerging antifungal therapies in real-world settings.

Cytomegalovirus (CMV) causes significant morbidity in CMV donor seropositive/recipient seronegative (D+R-) solid organ transplant recipients, but organ-specific differences in CMV epidemiology and the utility of laboratory surveillance after prophylaxis (SAP) are not well characterized. We performed a single-center retrospective study of 540 CMV D+R- heart (n = 145), kidney (n = 216), or liver recipients (n = 179) who received 6 months of CMV prophylaxis followed by SAP for 12 weeks and were followed for at least 24 months after transplant. The cumulative incidence of clinically significant CMV infection (csCMVi) was higher in heart and liver recipients than in kidney recipients (66%, 65%, and 48%, respectively; P < .001). The first csCMVi episode after prophylaxis completion occurred significantly later in heart recipients (median 97 days after prophylaxis completion; interquartile range [IQR], 59-179 days) compared with kidney (median 54 days; IQR, 37-116 days; P = .004) and liver recipients (median 46 days; IQR, 32-63 days; P < .001). Of 75 heart recipients with csCMVi, 41 (55%) did not develop csCMVi until after the 12-week SAP period. Heart recipients had delayed csCMVi onset, and prolonged surveillance may be required for SAP to meaningfully reduce CMV disease risk. Strategies that promote durable CMV immune control are needed, and studies evaluating these approaches should prioritize CMV D+R- heart recipients.

Antivirals form a foundation for protecting immunocompromised individuals (ICIs) from influenza complications. Neuraminidase inhibitors have demonstrated benefit for both prophylaxis and treatment in ICIs, including when given >48 hours after symptom onset. Baloxavir is a newer antiviral that has potent effects on viral kinetics in immunocompetent people, but data on baloxavir in ICIs are currently limited. Optimization of antiviral therapy to minimize viral replication within ICIs and reduce the risk of treatment-emergent antiviral resistance (eg, through combination regimens) may prevent viral evolution within ICIs and mitigate transmission of virulent or resistant variants to the general public. Unfortunately, ICIs have been excluded from most clinical trials evaluating novel influenza preventive and therapeutic strategies. Inclusion of ICIs in such clinical trials is essential to facilitate acquisition of clinical and virologic data in patients with specific immunocompromising conditions and ensure that ICIs have equitable access to valuable interventions.

Background:Persons with human immunodeficiency virus (PWH) are living longer, leading to increased end-organ disease from chronic illness. Organ transplantation improves survival in patients with end-organ disease yet remains a constrained resource due to limited access. We aimed to better understand barriers to transplantation for thoracic end-organ disease in PWH. Methods:We performed a retrospective study of patients referred to our center for consideration of thoracic organ transplant and assessed the factors associated with transplant eligibility in candidates with human immunodeficiency virus (HIV). We also assessed clinical outcomes in PWH progressing to transplant. Results:Over a 10-year period, 30 HIV-seropositive candidates and 10,905 HIV-seronegative candidates were referred to our center. Of candidates referred, 40% (12 of 30) of HIV-seropositive candidates were waitlisted compared to 20% (2,172 of 10,905) of HIV-seronegative candidates (p = 0.006). The median time from referral to waitlist activation in HIV-seropositive and HIV-seronegative candidates was similar (103 days vs 102 days, respectively; p = 0.92). Eight (27%) HIV-seropositive candidates underwent transplant compared to 1,962 (18%) HIV-seronegative candidates (p = 0.22). The median waitlist time in HIV-seropositive and HIV-seronegative candidates was similar (20 days vs 16 days, respectively; p = 0.98). Of the 8 HIV-seropositive transplant recipients, no recipient developed any HIV-associated complication, and 7 recipients (88%) survived beyond 1 year. Conclusions:HIV-seropositive thoracic transplant candidates were more likely to be waitlisted compared to HIV-seronegative candidates. Progression to transplant and waitlist times were similar between candidates with and without HIV. Our study suggests that HIV alone was not a significant barrier to transplantation in PWH when referred and evaluated for thoracic organ transplantation.

Early observations of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) transmission via lung transplantation have led to frequent discard of lungs from donors with positive SARS-CoV-2 tests. We compared survival between lung transplant recipients (LUTRs) with SARS-CoV-2 (+) (n = 11) and SARS-CoV-2 (-) donors (n = 192) transplanted from January 30, 2022 to March 31, 2024. Three of the 11 SARS-CoV-2 (+) donors had positive lower respiratory tract (LRT) tests. Two of their 3 recipients developed post-transplant SARS-CoV-2 infections, including one LUTR who died 11 days post-transplant. LUTRs with SARS-CoV-2 (+) donors had higher 30-day mortality (2/11 [18.2%] vs 7/192 [3.6%], p = 0.02), but there was no significant difference in 1-year mortality (2/11 [18.2%] vs 27/192 [14.1%], p = 0.56). Only 3 (27%) LUTRs with SARS-CoV-2 (+) donors developed acute cellular rejection in the first post-transplant year, and none were diagnosed with chronic lung allograft dysfunction. These findings support consideration of SARS-CoV-2 (+) lung donors, especially when LRT testing is negative.

BACKGROUND:Infectious complications are common in patients implanted with HeartMate 3 (HM3) left ventricular assist devices (LVAD). Despite these issues, some patients with LVAD-specific infection are ultimately considered for heart transplant (HT). The impact of HM3 LVAD-associated infection on postHT outcomes remains unclear. METHODS:We reviewed all adult patients who were listed for HT at Duke University Hospital between 1/1/2014 and 12/31/2024 (n = 1267) and identified 115 patients with a HM3 device who underwent HT. These 115 patients were further stratified based on pre-HT LVAD-specific infection. We assessed the impact of LVAD-specific infection on short-term postHT complications, including length of hospitalization, primary graft dysfunction (PGD), episodes of acute rejection, and occurrences of postHT hospitalization with infection up to 1-year. Kaplan-Meier analysis was used to assess risk of death after HT. RESULTS:Of the 115 patients, 59 patients (51%) had HM3 LVAD-specific infection prior to HT. Compared to patients without pre-HT LVAD-specific infection, there was no difference in 1 year post-HT survival (p = 0.14). Similarly, there was no difference in postHT length of stay (p = 0.435), treated acute rejection (p = 0.536), or severe PGD (p = 0.166). CONCLUSIONS:For carefully selected patients with HM3 LVAD-specific infections, HT appears to be a safe option without excess short-term morbidity or mortality HT.

Successful prevention and treatment of cytomegalovirus (CMV) infection remains a central focus of clinical care in solid organ transplantation (SOT) and allogeneic hematopoietic cell transplantation (HCT). Over the past 5 years, pivotal clinical trials have created new paradigms in CMV prevention, including diverging approaches in HCT and SOT. We review recent advances in CMV risk assessment and progress in antiviral and immune-based strategies for CMV prevention and treatment. We highlight approaches to optimize CMV-specific immunity through vaccination, monoclonal antibodies, and virus-specific T cells. Observational studies and interventional trials of commercially available CMV cell-mediated immunity assays for refining preventive and treatment strategies are summarized. Finally, we discuss the importance of enhancing CMV-specific immunity to mitigate the negative impacts of CMV in different transplant settings. CMV infections in recipients of chimeric antigen receptor-T (CAR-T) cell therapies and other immunocompromised populations are growing areas of importance that are beyond the scope of this review.

BACKGROUND:Early posttransplant cytomegalovirus (CMV) infections in CMV seronegative solid organ transplant recipients (SOTR) with CMV seronegative donors (D-/R-) are often attributed transfusion-transmitted CMV. The prevalence of false-negative donor CMV serology in D-/R- SOTR with early CMV infections has not been explored. METHODS:We determined the frequency and characteristics of CMV DNAemia that occurred within 90 days of transplant among adult SOTR classified as D-/R- who underwent a first SOT at a single center between February 25, 2014 and February 25, 2024. Repeat donor CMV antibody testing was performed on stored donor sera if possible. RESULTS:Thirteen of 737 (1.8%) D-/R- SOTR from 12 donors developed CMV DNAemia within 90 days of transplant (median time to DNAemia: 28 days, interquartile range 23-42 days). Five (38%) recipients experienced CMV disease either before (n = 2) or after (n = 3) CMV DNAemia was identified, and five (38%) developed CMV antiviral resistance mutations during their course. Repeat CMV antibody testing was performed on sera from four donors to five recipients and was positive in three (75%) tested donors. CONCLUSIONS:Early CMV infections in D-/R- SOTR are uncommon but associated with high morbidity. CMV transmission from organ donors with false negative CMV serology is an important source of early CMV infections in D-/R- SOTR. Clinicians should suspect and promptly report early CMV infections in D-/R- SOTR as potential donor-derived processes, regardless of donor and/or recipient transfusion histories. Reporting such cases is essential to promote broader investigations that may identify suboptimal donor CMV screening assays.

Machine perfusion strategies reduce the duration of organ ischemia and minimize tissue damage, increasing use of organs previously considered unsuitable for transplant. This review outlines the basic principles of organ preservation and machine perfusion, describes the risk of microbial contamination and role of antimicrobials during machine-based preservation, and discussed opportunities to leverage machine perfusion to reduce the risk of disease transmission. Ex situ machine perfusion (ESMP), which involves circulating perfusate through an organ’s vasculature to maintain physiological function, introduces new infectious considerations tied to its inherent function and real-world applications. Antimicrobials are routinely added to the perfusate in normothermic machine perfusion to mitigate the risk of microbial growth at normothermia. Microbial growth in ESMP perfusate has been described, but cultures often contain low-virulence organisms that do not predict post-transplant infection. Manipulation of organs on ESMP has been evaluated as a method to reduce the risk of infection transmission, but ESMP is not currently used for this purpose. Current data do not suggest that ESMP systems confer a clinically significant infection risk over traditional preservation methods, but large, multicenter, prospective studies are needed to better understand infection risk. Universal treatment of recipients with antimicrobials targeting preservation fluid cultures is likely to be unnecessary, but the benefits of targeted treatment of certain potential pathogens could outweigh the risks. ESMP offers a potential platform for targeting donor-derived pathogens, but optimization of ex situ manipulation will be required for it to be an effective infection prevention approach.

BACKGROUND:New and minimally invasive tools to aid the diagnosis of invasive fungal diseases (IFD) are urgently needed as the immunocompromised population at highest risk increases. Advancements in molecular technology have rendered new diagnostics more readily available for clinical use. METHODS:This case-control study used prospectively collected archived plasma specimens and data from the Aspergillus Technology Consortium Repository to investigate the diagnostic performance of microbial cell-free DNA (mcfDNA) sequencing as a minimally invasive diagnostic for IFDs in a population of high-risk immunocompromised hosts including hematologic malignancy, stem cell, and solid organ transplants patients. The 2008 Mycoses Study Group/European Organization for the Research and Treatment of Cancer diagnostic criteria served as the gold standard for test performance. RESULTS:Sixty-five adult subjects with proven or probable IFD and 65 controls without IFD were included. Among IFD episodes Aspergillus was the most common pathogen (70.8%, 46/65), followed by Mucorales (10.8%, 7/65). Overall, sensitivity was 47.7% and specificity was 100%. Sensitivity varied based on disease certainty and pathogen; sensitivity was higher in proven versus probable IFD (60.0% vs 37.1%, respectively) and higher for subjects with invasive mucormycosis (100%) compared with aspergillosis (45.7%). CONCLUSIONS:A positive result by mcfDNA sequencing may reduce the need for invasive sampling in patients with suspected IFD. In this exploratory analysis, its high sensitivity and specificity for invasive mucormycosis suggests it could be useful for early treatment and intervention of this IFD. Future studies should focus on understanding how specific factors impact the sensitivity of mcfDNA sequencing for invasive aspergillosis.