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Older kidney transplant recipients demonstrate increased rates of infection, and lower rates of rejection, compared with younger kidney transplant recipients. However, the mechanism behind this observation remains unknown. To develop a multifaceted view of age-associated immune dysfunction, we determined the function and phenotype of T cells predisposing to vulnerability to infection on a molecular level. Overlapping peptide pools representing the dominant CMV antigens were used to stimulate PBMC collected from 51 kidney transplant recipients, using cytokine secretion to determine specificity and intensity of response. Staphylococcal endotoxin B (SEB) was analyzed in parallel. To define immune cell subsets, we used single cell RNA sequencing (scRNAseq) to evaluate cellular surface markers and gene expression. We found increased frequency of SEB- and CMV-specific T cells was associated with freedom from infection, especially in older patients. Spatialized t-SNE analysis revealed decreased frequency of naïve T cells, increased frequency of TEMRA cells, and decreased frequency of IFNγ secreting T cells in patients with infection. Application of scRNAseq analysis revealed increased frequency of terminally differentiated T cells expressing NK-associated receptors and inhibitory markers. These findings offer unique insight into the mechanism behind vulnerability to infection in the kidney transplant recipient, revealing a specific T cell subtype of impaired antigen response and terminal effector phenotype as markers of T cell senescence.

BackgroundThe COVID-19 pandemic has caused significant morbidity and mortality in solid organ transplant (SOT) recipients. However, it remains unclear whether the risk factor for SOT patients is the immunosuppression inherent to transplantation versus patient comorbidities.MethodsWe reviewed outcomes in a cohort of SOT (n=129) and non-SOT (NSOT) patients (n=708) admitted to the University of California, Los Angeles for COVID-19 infection. Data analyses utilized multivariate logistic regression to evaluate the impact of patient demographics, comorbidities, and transplant status on outcomes. SOT patients were analyzed by kidney SOT (KSOT) versus nonkidney SOT (NKSOT) groups.ResultsSOT and NSOT patients with COVID-19 infection differed in terms of patient age, ethnicity, and comorbidities. NKSOT patients were the most likely to experience death, with a mortality rate of 16.2% compared with 1.8% for KSOT and 8.3% for NSOT patients (p=.013). Multivariable analysis of hospitalized patients revealed that patient age (odds ratio [OR] 2.79, p=.001) and neurologic condition (OR 2.66, p&nbsp

Frailty is common and is associated with increased mortality, lower quality of life, and higher readmission rates in cirrhotic patients. Not only are these outcomes important, but further understanding the impact of frailty on a caregiver’s life is crucial to better comprehend caregiver burden in cirrhotic patients and develop strategies to improve care for patients and their caregivers. A single-center, prospective study was conducted of cirrhotic patients and their caregivers between 4/1/2019 and 11/1/2019. Frailty testing combined aspects from the Fried Frailty Instrument, Short Physical Performance Battery, and activities of daily living. Caregivers completed questionnaires to evaluate caregiver burden using the Zarit Burden Interview (ZBI-12), and perceived social support, using the Interpersonal Support Evaluation List. In total, 94 cirrhotic patients were included, 50% males with a median age of 63.1 years. The most common etiology of cirrhosis was nonalcoholic steatohepatitis. Frailty was prevalent (45.1%). In total, 12.8% of caregivers reported a high burden based on ZBI-12. There was no association between frailty and caregiver burden, hospitalization rates, or death. However, frailty was associated with a higher number of outpatient GI visits (p = 0.002). Lower perceived social support among caregivers was associated with a higher caregiver burden (p

Purpose We reviewed the clinical experience of kidney transplant recipients diagnosed with severe acute respiratory syndrome coronavirus 2 infection in order to understand the impact of the current coronavirus disease 2019 (COVID-19) pandemic infection on transplant recipients. Given that early reports from heavily affected areas demonstrated a very high mortality rate amongst kidney transplant recipients, ranging between 30% and 40%, we sought to evaluate outcomes at a center with a high burden of cases but not experiencing acute crisis due to COVID-19. Procedures In this single center retrospective observational study, medical records of all kidney transplant recipients at the UCLA Medical Center were reviewed for a diagnosis of COVID-19 by polymerase chain reaction, followed by chart review to determine kidney transplant characteristics and clinical course. Main findings A total of 41 kidney transplant recipients were identified with COVID-19 positive polymerase chain reaction. Recipients had been transplanted for a median of 47 months before diagnosis. The large proportion of infected individuals were minorities (Hispanic 65.9%, black 14.6%), on prednisone, tacrolimus, and mycophenolate mofetil (95.1%, 87.8%, and 87.8%, respectively), and had excellent allograft function (median 1.25 mg/dL). The most common presenting symptoms were fever, dyspnea, or cough. Most patients were hospitalized (63.4%); mortality was 9.8% and occurred only in patients in the intensive care unit. The most common treatment was reduction or removal of antimetabolite (77.8%). Approximately 26.9% presented with AKI. Conclusions COVID-19 infection in kidney transplant recipients results in a higher rate of hospitalization and mortality than in the general population. In an area with a high number of infections, the mortality rate was lower compared with earlier reports from areas experiencing early surge and strain on the medical system. Minorities were disproportionately affected. Future studies are needed to determine optimal approach to treatment and management of immunosuppression in kidney transplant recipients with COVID-19 infection.

Purpose of review The aim of this review is to describe the latest investigations into the immunobiology of aging and the potential impact on outcomes after mechanical circulatory support implantation and heart transplantation. This information is relevant given the growing numbers of older patients with heart failure undergoing evaluation for mechanical circulatory support device (MCSD) or heart transplantation. Recent findings A host of aging-associated aspects of immune dysfunction have been described in the general population including T-cell senescence, exhaustion, and terminal dedifferentiation, as well as impaired function of innate immune cells. Another important consequence of T-cell senescence is inflammation, which is known to have a strong relationship with both heart failure and frailty in older patients. Recent data on the association between T-cell and monocyte phenotypes as well as evaluation of gene expression and adverse outcomes after MCSD suggests the potential value of immunologic assessment of MCSD and heart transplant candidates and recipients. Measurement of physical frailty represents another avenue for patient evaluation that may complement immunologic assessment. Determination of immune dysfunction and frailty prior to transplantation may have implications for choice of induction and dosing of maintenance immunosuppression. Summary As the age of transplant and MCSD candidates and recipients continues to increase, it is important for providers to recognize the potential impact of aging-associated immune dysfunction and how it may influence candidate selection, postintervention monitoring, and adjustment of immunosuppression.

Cytomegalovirus (CMV) causes mostly asymptomatic but lifelong infection. Primary infection or reactivation in immunocompromised individuals can be life-threatening. CMV viremia often occurs in solid organ transplant (SOT) recipients and associates with decreased graft survival and higher mortality. Furthering understanding of impaired immunity allowing CMV reactivation is critical to guiding anti-viral therapy and examining CMV's impact on outcomes of SOT. This study characterized longitudinal immune responses to CMV in 31 kidney transplant recipients with CMV viremia and matched, non-viremic recipients. Subjects were sampled three- and twelve-months post-transplant, with additional samples one-week and one-month post-viremia. Peripheral blood mononuclear cells (PBMC) were stained for NK and T cell markers. PBMC transcriptomes were characterized by RNA-Seq. Plasma proteins were quantified by Luminex. CD8 T cell transcriptomes were characterized by single-cell RNA-Seq. Pre-viremia, patients had high levels of IL-15 with concurrent expansion of immature CD56bright NK cells. Post-viremia, mature CD56dim NK cells and CD28- CD8 T cells upregulating inhibitory and NK-associated receptors were expanded. Phenotype of NK cells and CD28- CD8 T cells were associated with control of viremia. These findings suggest signatures of innate activation may be prognostic for CMV reactivation post-transplant, while CD8 T cell functionality is critical for effective control of CMV.

Prior research has identified frailty, comorbidity, and age as predictors of outcomes for patients with coronavirus disease 2019 (COVID-19), including mortality. However, it remains unclear how these factors play different roles in COVID-19 prognosis. This study focused on correlations between frailty, comorbidity and age, and their correlations to discharge outcome and length-of-stay in hospitalized patients with COVID-19. Clinical data was collected from 56 patients who were ≥50 years old and admitted from March 2020 to June 2020 primarily for COVID-19. Frailty Risk Score (FRS) and the Charlson Comorbidity Index (CCI) were used for assessment of frailty and comorbidity burden, respectively. Age had significant positive correlation with FRS and CCI (P .001, P .001, respectively). There was also significant positive correlation between FRS and CCI (P .001). For mortality, patients who died during their hospitalization had significantly higher FRS and CCI (P = .01 and P .001, respectively) but were not significantly older than patients who did not. FRS, CCI, and age were all significantly associated when looking at overall adverse discharge outcome (transfer to other facility or death) (P .001, P = .005, and P = .009, respectively). However, none of the 3 variables were significantly correlated with length-of-stay. Multivariate analysis showed FRS (P = .007) but not patient age (P = .967) was significantly associated with death. We find that frailty is associated with adverse outcomes from COVID-19 and supplants age in multivariable analysis. Frailty should be part of risk assessment of older adults with COVID-19.

Frailty, defined as a state of decreased physiologic reserve, has been correlated with poorer outcomes after hospitalization or surgery. Studies in lung transplant patients have associated frailty with an increased risk of post-transplant mortality; however, a unified approach is lacking. The identification of frail patients can help clinicians pre-emptively target modifiable risk factors and may facilitate risk stratification. The Frailty Risk Score (FRS) is a chart review-based approach based on eight symptoms and four laboratory biomarkers. We applied this method in a retrospective study to investigate its utility in predicting post-transplant lung outcomes. Eighty-four lung transplant recipients were evaluated, including 51 older (≥ 60) and 33 younger (

Fungus account for ∼ 5% of all cases infections following solid organ transplant. Fungal infections in the setting of immunosuppression may progress rapidly and present in an atypical pattern. Herein we describe 4 cases of environmental fungal infections acquired decades prior to transplant that developed into localized atypical cutaneous masses following kidney transplant.

Purpose of review To describe the latest investigations into the role of frailty and assessment of other aging-related issues in the solid organ transplant candidate and recipient. This information is relevant for all involved in the care of transplant patients, but is especially relevant in infectious diseases, given the increased burden of infection seen in older and frailer patients. Recent findings The Fried Frailty Phenotype (FFP) and Short Performance Physical Battery (SPPB) are well validated tools for measuring frailty in older adults. Recently, these frailty tools have also been used to predict a range of clinical outcomes in adults with endstage organ disease undergoing advanced therapies including mechanical circulatory device (MCSD) or transplantation including death on the waiting list, length of hospital stay, need for readmission, infection, and death. Frailty may also be estimated by chart review and comorbidity assessment. Other aging-related evaluations of interest are cognitive function, sarcopenia, and nutritional status. The strength of association for each tool varies by the type of end organ disease, although there are many findings in common across organ types. Summary As trends in the aging of the population continue to impact transplant and MCSD candidates and recipients, it is increasingly important for providers to be cognizant of the methods for assessment of aging-associated dysfunction including frailty and sarcopenia.

Purpose of review This review is a brief overview of current guidelines on screening donors and candidates for bacterial, fungal, parasitic and viral infections prior to solid organ transplantation. The pretransplant period is an important time to evaluate infection exposure risk based on social history as well as to offer vaccinations. Recent findings One of the major changes in the past few years has been increased utilization of increased Public Health Service risk, HIV positive, and hepatitis C-positive donors. There has also been increased attention to donor and recipient risks for geographically associated infections, such as endemic fungal infections and flaviviruses. Summary Screening for donors and candidates prior to organ transplantation can identify and address infection risks. Diagnosing infections in a timely manner can help guide treatment and additional testing. Use of necessary prophylactic treatment in organ recipients can prevent reactivation of latent infections and improve posttransplant outcomes.

Background Older kidney patients with chronic kidney disease benefit significantly from kidney transplantation. However, these older transplant recipients have greater mortality after transplantation than younger transplant recipients. Understanding the impact of comorbidities on post-transplant mortality can improve risk stratification and patient selection. Methods A single-center analysis of 3105 kidney transplant recipients was performed over a 12-year period. Comorbidities associated with death were evaluated in older and younger transplant recipients. Results The 2 most important factors associated with increased mortality in the first 100 days after transplant were recipient age ≥60 and receipt of deceased donor organs (adjusted odds ratios, 3.29 and 5.80, respectively), with no statistically significant impact of recipient comorbidities. In the later post-transplant period (after the first 100 days), recipient age ≥60 and receipt of deceased donor organs (adjusted hazard ratios [HR] of 2.14 and 2.29, respectively) remained predictors of mortality. We also found that donor age ≥60 and the recipient having cardiovascular disease and diabetes were independent predictors of increased mortality. There was a statistically significant interaction between diabetes and heart disease and recipient age ≥60, with a lesser impact on late mortality in older patients compared to younger patients. Conclusions This analysis suggests that comorbidities have a larger impact later after transplantation, with less effect on older recipients. These observations suggest that certain comorbid conditions should be evaluated differently in older patients compared to younger ones.

A consensus conference on frailty in kidney, liver, heart and lung transplantation, sponsored by the American Society of Transplantation (AST) and endorsed by the American Society of Nephrology (ASN), the American Society of Transplant Surgeons (ASTS) and the Canadian Society of Transplantation (CST), took place on February 11, 2018 in Phoenix, Arizona. Input from the transplant community through scheduled conference calls enabled wide discussion of current concepts in frailty, exploration of best practices for frailty risk assessment of transplant candidates and for management after transplant, and development of ideas for future research. A current understanding of frailty was compiled by each of the solid organ groups and is presented in this paper. Frailty is a common entity in patients with end-stage organ disease who are awaiting organ transplantation, and affects mortality on the wait-list and in the post-transplant period. The optimal methods by which frailty should be measured in each organ group are yet to be determined, but studies are underway. Interventions to reverse frailty vary among organ groups and appear promising. This conference achieved its intent to highlight the importance of frailty in organ transplantation and to plant the seeds for further discussion and research in this field.

Noninvasive immunologic analysis of peripheral blood holds promise for explaining the mechanism of development of adverse clinical outcomes, and may also become a method for patient risk stratification before or after mechanical circulatory support device (MCSD) implantation. Dysregulation of the innate immune system is associated with increased patient age but has yet to be evaluated in the older patient with advanced heart failure undergoing MCSD surgery. Patients pre- and post-MCSD implantation had peripheral blood mononuclear cells (PBMC) and serum isolated. Multiparameter flow cytometry was used to analyze markers of innate cell function, including monocyte subtypes. Multiplex cytokine analysis was performed. MELD-XI and SOFA scores were utilized as surrogate markers of outcomes. Increased levels of pro-inflammatory cytokines including IL-15, TNF-α, and IL-10 were associated with increased MELD-XI and SOFA scores. IL-8, TNF- α, and IL-10 were associated with risk of death after MCSD implantation, even with correction for patient age. Increased frequency of ‘classical’ monocytes (CD14 + CD16−) were associated with increased MELD-XI and SOFA scores. This suggests that inflammation and innate immune system activation contribute to progression to multiorgan system failure and death after MCSD surgery. Development of noninvasive monitoring of peripheral blood holds promise for biomarker development for candidate selection and patient risk stratification.

Beyond its widely recognized morbidity and mortality, coronavirus disease 2019 poses an additional health risk to renal allograft recipients. Detection and measurement of donor-derived cell-free DNA (dd-cfDNA), expressed as a fraction of the total cell-free DNA (cfDNA), has emerged as a noninvasive biomarker for allograft rejection. Here, we present a case report of a patient who was infected with severe acute respiratory syndrome coronavirus 2, 11 mo post-kidney transplant. The patient was serially monitored using an analytically and clinically validated massively multiplex PCR-based dd-cfDNA assay to assess allograft injury and risk for rejection. Over the course of infection, low dd-cfDNA fractions were observed (below the 1% cutoff) and were accompanied by unusually highly elevated levels of total cfDNA, which gradually declined as the infection resolved. The case study highlights the variability in total cfDNA levels during and after viral infection, and the need to consider both total and dd-cfDNA levels when clinically interpreting the results for allograft rejection. Furthermore, the study highlights the importance of serial testing, wherein an interplay between total cfDNA and dd-cfDNA can inform the optimization of a patient's immunosuppressive treatment regimen in response to infection.

After kidney transplantation, infection and death are important clinical complications, especially for the growing numbers of older patients with limited resilience to withstand adverse events. Evaluation of changes in gene expression in immune cells can reveal the underlying mechanisms behind vulnerability to infection. A cohort of 60 kidney transplant recipients was evaluated. Gene expression in peripheral blood mononuclear cells 3months after kidney transplantation was analyzed to compare differences between patients with infection and those who were infection-free in the first-year post-transplant. Pro-inflammatory genes such as IL1B, CCL4, and TNF were found to be downregulated in post-transplant PBMC from patients who developed infection. In contrast, genes involved in metabolism, HLA genes, and transcripts involved in type I interferon innate antiviral responses were found to be upregulated. Promoter-based bioinformatic analyses implicated increased activity of interferon regulatory factors, erythroid nuclear factor (E2), and CCAAT-enhancer-binding protein (C/EBP) in patients who developed infections. Differential patterns of gene expression were observed in patients who developed infection after kidney transplantation, with patterns distinct from changes associated with patient age, suggesting possible mechanisms behind vulnerability to infection. Assessment of gene expression in blood may offer an approach for patient risk stratification and monitoring after transplantation.

Many lung transplant candidates and recipients are older and frailer compared to previous eras. Older patients are at increased risk for pre- and post-transplant mortality, but this risk is not explained by numerical age alone. This manuscript represents the product of the American Society of Transplantation (AST) conference on frailty. Experts in the field reviewed the latest published research on assessment of elderly and frail lung transplant candidates. Physical frailty, often defined as slowness, weakness, low physical activity, shrinking, and exhaustion, and frailty evaluation is an important tool for evaluation of age-associated dysfunction. Another approach is assessment by cumulative deficits, and both types of frailty are common in lung transplant candidates. Frailty is associated with death or delisting before transplant, and may be associated with post-transplant mortality. Sarcopenia, cognitive dysfunction, depression, and nutrition are other important components for patient evaluation. Aging-associated inflammation, telomere dysfunction, and adaptive immune system senescence may also contribute to frailty. Developing tools for frailty assessment and interventions holds promise for improving patient outcomes before and after lung transplantation.

BackgroundCytomegalovirus (CMV) infection continues to negatively affect outcomes for solid organ transplant recipients, despite the advent of strategies for preemptive surveillance and prophylaxis. The impact is especially great for CMV seronegative recipients of donor seropositive organs, who typically lack the ability to control CMV infection at the time of transplantation.MethodsWe reviewed episodes of CMV DNAemia in a modern cohort of kidney transplant recipients over a 3-year period at a high-volume transplant center to investigate the frequency of DNAemia during antiviral prophylaxis.ResultsDespite receipt of antiviral prophylaxis per current guidelines, 75 cases of CMV DNAemia were observed in the first 100days after transplantation. For high risk patients, median time to DNAemia was 75days after transplantation, and the majority of patients had experienced dose-reduction of valganciclovir due to renal insufficiency. Review of CMV seropositive intermediate risk patients demonstrated DNAemia occurring earlier after transplantation compared with high risk patients with a median time of 64days (P=.029). The impact of valganciclovir dose adjustment was less notable in the intermediate risk group.ConclusionsGuidelines recommend beginning routine surveillance for CMV after the completion of antiviral prophylaxis. Our findings suggest that closer monitoring may be beneficial, especially for high risk patients at risk for DNAemia. Patients requiring dose adjustment of valganciclovir due to renal insufficiency may be at increased risk for CMV DNAemia. Improved methods for CMV prophylaxis and evaluation of immunologic risk for CMV DNAemia and disease are needed to improve patient outcomes after kidney transplantation.

The infectious disease Coronavirus Disease 2019 (COVID‐19) was declared a pandemic by the World Health Organization in March 2020. The impact of COVID‐19 on solid organ transplantations, including heart transplantation, is currently unclear. Many transplant programs have been forced to swiftly re‐evaluate and adapt their practices, leading to a marked decrease in transplants performed. This trend has been due to various factors, including increased donor COVID‐19 screening scrutiny and recipient waiting list management in anticipation of COVID‐19 critical care surge capacity planning. In the face of these unknown variables, determining when and how to proceed with transplantation in our population of patients with end‐stage cardiomyopathies is challenging. Here, we describe our center’s experience with orthotopic heart transplantation (OHT) in one of the country’s pandemic epicenters, where we performed eight OHTs in the first two months after community spread began in late February 2020.

Supplemental Digital Content is available in the text., Background. Older kidney transplant recipients demonstrate increased rates of infection but decreased rates of rejection compared with younger recipients, suggesting that older transplant patients are functionally overimmunosuppressed. We hypothesized that this is a consequence of reduction in immunological activity due to biological aging and that an immune biological age, as determined by DNA methylation (DNAm), would be associated more strongly with incidence of infection than chronological age. Methods. DNAm analysis was performed on peripheral blood mononuclear cell collected from 60 kidney transplant recipients representing older (≥age 60 y) and younger (aged 30–59 y) patients 3 months after transplantation. DNAm age was calculated based on methylation status of a panel of CpG sites, which have been previously identified as indicative of biological age. Results. Correlation was seen between chronological and DNAm age; however, there were many patients with significant differences (either acceleration or slowing) between DNAm age and chronological age. A statistically significant association was seen between increased DNAm age and incidence of infection in the first year after kidney transplantation, whereas no significant association was seen between chronological age and infection. Conclusions. Assessment of DNAm age holds promise as an approach for patient evaluation and individualization of immune suppression regimens. This analysis may provide insights into the immunological mechanism behind increased incidence of infection observed in older transplant patients. The ability to measure biological age would allow for patient risk stratification and individualization of immunosuppression, improving outcomes for the growing numbers of older patients undergoing kidney transplantation.

Background Survival after heart transplantation (HTx) is limited by complications related to alloreactivity, immune suppression, and adverse effects of pharmacologic therapies. We hypothesize that time-dependent phenomapping of clinical and molecular data sets is a valuable approach to clinical assessments and guiding medical management to improve outcomes. Methods We analyzed clinical, therapeutic, biomarker, and outcome data from 94 adult HTx patients and 1,557 clinical encounters performed between January 2010 and April 2013. Multivariate analyses were used to evaluate the association between immunosuppression therapy, biomarkers, and the combined clinical end point of death, allograft loss, retransplantation, and rejection. Data were analyzed by K-means clustering (K = 2) to identify patterns of similar combined immunosuppression management, and percentile slopes were computed to examine the changes in dosages over time. Findings were correlated with clinical parameters, human leucocyte antigen antibody titers, and peripheral blood mononuclear cell gene expression of the AlloMap (CareDx, Inc., Brisbane, CA) test genes. An intragraft, heart tissue gene coexpression network analysis was performed. Results Unsupervised cluster analysis of immunosuppressive therapies identified 2 groups, 1 characterized by a steeper immunosuppression minimization, associated with a higher likelihood for the combined end point, and the other by a less pronounced change. A time-dependent phenomap suggested that patients in the group with higher event rates had increased human leukocyte antigen class I and II antibody titers, higher expression of the FLT3 AlloMap gene, and lower expression of the MARCH8 and WDR40A AlloMap genes. Intramyocardial biomarker-related coexpression network analysis of the FLT3 gene showed an immune system–related network underlying this biomarker. Conclusions Time-dependent precision phenotyping is a mechanistically insightful, data-driven approach to characterize patterns of clinical care and identify ways to improve clinical management and outcomes.

Immunologic impairment may contribute to poor outcomes after implantation of mechanical circulatory support device (MCSD), with infection often as a terminal event. The study of immune dysfunction is of special relevance given the growing numbers of older patients with heart disease. The aim of the study was to define which immunologic characteristics are associated with development of adverse clinical outcomes after MCSD implantation. We isolated peripheral blood mononuclear cells (PBMC) from patients pre- and up to 20 days post-MCSD implantation and analyzed them by multiparameter flow cytometry for T cell dysfunction, including terminal differentiation, exhaustion, and senescence. We used MELD-XI and SOFA scores measured at each time point as surrogate markers of clinical outcome. Older patients demonstrated increased frequencies of terminally differentiated T cells as well as NKT cells. Increased frequency of terminally differentiated and immune senescent T cells were associated with worse clinical outcome as measured by MELD-XI and SOFA scores, and with progression to infection and death. In conclusion, our data suggest that T cell dysfunction, independently from age, is associated with poor outcomes after MCSD implantation, providing a potential immunologic mechanism behind patient vulnerability to multiorgan dysfunction and death. This noninvasive approach to PBMC evaluation holds promise for candidate evaluation and patient monitoring.

Purpose Our previous studies demonstrated an association between physical frailty by Fried frailty phenotype (FFP) with waitlist death and length of stay (LOS) after lung transplantation. We sought to evaluate the predictive ability of sarcopenia in patients undergoing evaluation for lung transplantation. Methods We identified 68 patients, ages 60-71, who had frailty evaluation by FFP or short performance physical battery (SPPB) with chest CT available for review during transplant evaluation. Using the software Osirix (Pixmeo, Switzerland), we determined the total area (in cm2) and average attenuation (in HU) of the right and left pectoralis muscle at the level of one slice above the aortic arch (Figure). Pectoralis was chosen as it resulted in more reproduceable measurements compared with intercostal muscles. Results Sarcopenia, as measured by either total pectoral area or average attenuation, was not significantly associated with patient age or physical frailty by FFP or SPPB. Sarcopenia was not associated with death on the waiting list or death in the first year after transplantation. Notably, however, patients with less sarcopenia were more likely to be transplanted (p= 0.022), a clinical outcome that was not associated with age, sex, or physical frailty. For patients who underwent transplantation during the period of study (n= 46), both lower total pectoral area and average attenuation were significantly associated with increased LOS after transplantation (p=0.002 and p=0.034, respectively). Conclusion Sarcopenia represents an attractive avenue for patient assessment, where chest CT evaluation is part of routine evaluation. No association was seen between physical frailty and sarcopenia, although both measures were predictive of clinical outcomes. This suggests the possibility of applying multiple assessments for patient risk stratification. Future studies are needed to determine the impact of optimizing nutrition and physical therapy in waitlisted patients.

BackgroundBK virus infection remains an important cause of loss of allograft function after kidney transplantation. We sought to determine whether polyfunctional T cells secreting multiple cytokines simultaneously, which have been shown to be associated with viral control, could be detected early after start of BK viremia, which would provide insight into the mechanism of successful antiviral control.MethodsPeripheral blood mononuclear cells collected during episodes of BK viral replication were evaluated by multiparameter flow cytometry after stimulation by overlapping peptide pools of BK virus antigen to determine frequency of CD8+ and CD4+ T cells expressing 1 or more cytokines simultaneously, as well as markers of T-cell activation, exhaustion, and maturation.ResultsBK virus controllers, defined as those with episodes of BK viremia of 3 months or less, had an 11-fold increase in frequency of CD8+ polyfunctional T cells expressing multiple cytokines, as compared with patients with prolonged episodes of BK viremia. Patients with only low level BK viremia expressed low frequencies of polyfunctional T cells. Polyfunctional T cells were predominantly of the effector memory maturation subtype and expressed the cytotoxicity marker CD107a.ConclusionsNoninvasive techniques for immune assessment of peripheral blood can provide insight into the mechanism of control of BK virus replication and may allow for future patient risk stratification and customization of immune suppression at the onset of BK viremia.

Background Cytomegalovirus (CMV) is one of the most common infections after transplantation and continues to cause significant morbidity and mortality. Current guidelines recommend 3-6 months of post-transplant prophylaxis with 900mg daily of valganciclovir in heart transplant recipients. At our institution, however, the protocol is to use 450mg daily of valganciclovir for 6-12 months for intermediate risk (R+) patients and 900 mg daily for high risk (D+/R-) patients. In this study we aimed to identify underlying patient characteristics associated with detectable viral load above the quantifiable threshold. Table 1. Comparison of patients with a CMV viral above and below 137. Methods We retrospectively reviewed medical records of adult (≥ 18 years) heart transplant recipients with detectable CMV viremia from 2016-2018 resulted during routine clinical screening. Results Ninety-seven heart transplant recipients with a detectable CMV viral load were identified. Of those, 38 (37.2%) had a quantifiable viral load above the 137 IU/mL threshold. When compared to the individuals with a detectable viral load below the threshold (< 137 IU/mL), they had similar age at time of transplant, increased likelihood of donor/recipient CMV IgG mismatch, and were more frequently on 900mg daily of prophylaxis at time of viremia. Of the individuals with CMV DNAemia above the threshold, the median time to viremia was 271.4 days and the median peak viral load was 701 IU/mL. When limiting analysis to only recipients who were CMV IgG positive, patients with viremia had similar age and more likely to be on 900mg daily of valganciclovir as prophylaxis when compared to individuals with CMV viremia < 137 IU/mL. When comparing CMV D+/R- patients, age and rates of 900mg valganciclovir as prophylaxis were similar (Table 1). Conclusion We found that despite receipt of CMV prophylaxis, an appreciable number of both R+ and D-/R+ heart transplant recipients developed breakthrough DNAemia despite being on prophylaxis of valganciclovir as recommended by guidelines. Despite receipt of the higher 900 mg daily dose, high risk patients had higher rates of breakthrough DNAemia at our institution compared with R+ intermediate risk patients. More research is needed to evaluate the optimal dose and duration for prophylaxis in heart transplant patients against CMV. Disclosures All Authors: No reported disclosures

Purpose Prior studies demonstrate that lung transplant recipients (LTRs) experience the highest rate of invasive mold infections amongst all transplant recipients. Aspergillosis is the most common offender, and aspergillus colonization and invasive disease have been linked to chronic lung allograft dysfunction (CLAD). There are no standardized guidelines regarding fungal prophylaxis strategy or agent selection. This study examined the relationship between post-transplant antifungal prophylaxis and freedom from CLAD. Methods This single-center retrospective analysis evaluated 566 adult LTRs from July 2, 2005 to December 28, 2015. Fungal prophylaxis practices evolved during the study period from targeted antifungal prophylaxis (TAP) to universal antifungal prophylaxis (UAP) for the first 6 months post-transplant with either voriconazole or posaconazole. A Kaplan-Meir analysis and Cox regression were performed to estimate freedom from CLAD at 3 years for TAP versus UAP patients. A similar approach was used to examine the relationship between freedom from CLAD and discharge antifungal selection (none, voriconazole, or posaconazole). Results Freedom from CLAD at 3 years post-transplant in the TAP versus UAP cohorts was 65% and 68%, respectively (P=0.35). The relative risk of CLAD was not significantly reduced in the UAP cohort even when adjusting for pre-transplant disease, transplant type, and induction therapy (hazard ratio 0.83; 95% confidence interval 0.63-1.13; P=0.24). Freedom from CLAD at 3 years post-transplant with patients grouped by discharge antifungal regimen was as follows: no prophylaxis 67%, voriconazole 68%, and posaconazole 70% (P=0.65). There was also no significant difference in risk of CLAD across patients grouped by discharge antifungal regimen following multivariable adjustment. Conclusion There was no significant difference in freedom from CLAD at 3 years post-transplant for LTRs managed under a TAP versus UAP strategy or for these patients when grouped by discharge antifungal regimen. These results, while unexpected, pique interest in further investigation, particularly elucidating the relationship between prophylaxis and incidence of fungal colonization and invasive disease. Pursuing these avenues of study will advance our understanding of the utility and benefit of fungal prophylaxis in the LTR population.

Background Frailty is a widely used measure in older patients as a predictor of poor outcomes after hospitalization and surgery. There is a growing body of data in kidney transplantation suggesting frailty can predict adverse outcomes. There is interest in using chart review measures of frailty and multimorbidity, as they may be equally predictive as physical measurement. This approach holds promise for patient evaluation, identifying candidates for prehabilitation, and targeting resources towards those anticipated to have an increased rate of clinical challenges after kidney transplantation. Frail patients who are often older may place a large resource and economic burden on transplant programs. Methods We applied a previously published chart review–based approach in a retrospective, pilot study to calculate the Frailty Risk Score (FRS) utilizing a cohort of kidney transplant patients. We reviewed concurrent comorbidities using the Charlson comorbidity (CM) score to determine the feasibility and utility of applying this approach in transplant patients to predict post-transplant outcomes such as length of hospitalization and the need for rehospitalization. Results Sixty kidney transplant recipients were evaluated by chart review, 23 characterized as older (> = 60) and 37 younger (ages 30–59). Median FRS score was 3 (range 1–7). Higher FRS was significantly associated with increased patient age (high FRS 19% in younger patients, 43% in older patients). Increased CM score was also associated with increased patient age. Patients with a high FRS stayed in the hospital for an average of 8 days, compared with 5.7 days for a low FRS. Patients with high FRS were readmitted an average of 2.9 times compared with an average of 1.1 for those with a low FRS. FRS score remained significant for predicting outcomes after adjustment for patient age. Conclusion Elevated FRS prior to transplantation was associated with increased hospital stay and the need for readmission in kidney transplant recipients. This analysis demonstrates the potential strength of chart review in evaluating frailty prior to transplantation, permitting risk stratification and targeting of resources for rehabilitation and close post-transplant monitoring. Frail patients may benefit from targeted “prehabilitation” to attenuate the associated adverse clinical outcomes.

Background Allosensitization during mechanical circulatory support (MCS) is a well-described phenomenon, although its mechanism remains unknown. Although immune-mediated interactions from devices or blood transfusions have been proposed, the role of inflammation in this development is less clear. This study was undertaken to further investigate the temporal association of cytokines and B-cell phenotypes in the MCS population. Methods Adult patients who received the Heartmate II (Thoratec, Pleasanton, Calif) at our center between September 2012 and March 2015 were prospectively followed after device implantation. Blood draws for anti-human leukocyte antigen (HLA) antibody, cytokine expression, and B-cell immunophenotyping were performed before implantation and for 3 weeks postoperatively. Time courses for cytokines and B-cell subsets were expressed using visual representations of median levels as heat maps, and mixed modeling analysis was used to model changes with time and patient factors. Results Twenty patients who received the Heartmate II (Thoratec) were analyzed during the study period. Four patients showed measureable levels of anti-HLA antibody during the follow-up period, although 3 of these had evidence of antibodies preoperatively. Analysis of cytokine trends revealed early (interleukin [IL]-6, IL-8, and IL-10) and late peaking (IL-3, IL-4, fibroblast growth factor 2, and CD40L) patterns. Upregulation of switched memory, transitional, and plasma blast B cells occurred over time. Right ventricular assist device use and low Interagency Registry for Mechanically Assisted Circulatory Support score were associated with decreased mature naive and increased antibody-secreting cells. Conclusions MCS device implantation was associated with increased inflammatory cytokines and maturation of B-cell phenotypes. No patients developed de novo HLA antibodies, whereas several showed increases in anti-HLA antibody levels detected before implantation. This suggests that inflammation and maturation of existing sensitized B cells might play an important role in the pathogenesis of allosensitization in MCS.

Purpose Frailty is associated with increased mortality in lung transplant candidates, but its association with infections during the post-transplant period is unknown. We sought to determine if there was an association between frailty and incidence of pneumonia after lung transplantation. Methods Pre-transplant frailty in transplant candidates over age 55 was evaluated by the Short Physical Performance Battery (SPPB) and Fried Physical Phenotype (FPP). Positive respiratory cultures (sputum, tracheal aspirate, BAL) up to 3 months post-transplant were reviewed. Presence of pneumonia was determined by physician documentation of “pneumonia” or “infection” in the medical record. Results 47 lung transplant recipients had frailty testing available. Among the 13 nonfrail (NF) lung transplant recipients by SPPB, 8 (62%) had positive respiratory cultures and 2 (15%) pneumonia, compared to 19 (63%) positive cultures and 6 (20%) cases of pneumonia in the prefrail (PF) group and 2 (67%) positive cultures and 1 (33%) pneumonia in the frail (F) group. Results were similar with frailty assessed by FFP, with 15 PF candidates of whom 11 (69%) had positive respiratory cultures and 2 (13%) had pneumonia, and 26 F patients, of whom 15 had positive cultures (58%) and 4 pneumonia (15%). Frailty was not significantly associated with pneumonia by SPPB (p= 0.73) or FFP (p=0.23). Identified species in colonization and infection varied by frailty category (Figure). Interestingly, an association was seen between cultures positive for Pseudomonas and frailty by FFP (p=0.015). Pneumonia but not colonization was significantly associated with death (p=0.009), suggesting that our chart-based definition was clinically relevant. Conclusion Pre-transplant frailty is not associated with pneumonia as assessed by chart review in the 3 months after transplantation. Future studies will examine whether this evaluation is confirmed in a larger patient cohort, and whether an association might exist for specific species.

Purpose Frailty is the deterioration of physiological reserve, decreasing resiliency to health stressors. Frail patients awaiting heart transplant are at risk for adverse outcomes after transplant, but the optimal way to assess frailty prior to transplant remains unknown. This study examined the relationship between physical and chart review based frailty assessments in heart transplant candidates and evaluated each assessment with respect to transplant status. Methods In this single-center, observational study, 44 heart transplant candidates were assessed for frailty using three methods. Short Physical Performance Battery (SPPB) and Fried Frailty Phenotype (FFP) were used as two physical assessments of frailty. Frailty Risk Score (FRS) was used as a chart review assessment of 20 different biopsychosocial and functional components, including biomarkers, depression, social support, cognitive impairment and sleep. We then determined the correlation between SPPB, FFP, and FRS and the difference in frailty status for three clinical outcomes: waitlist status, transplant status and mortality. Results Of 44 participants, mean age was 60 years. Mean SPPB score was 7.1 out of 12, mean FFP score was 3.1 out of 5, and mean FRS was 7.1 out of 20. FRS significantly correlated with SPPB and FFP (R2 = 0.101, p = 0.043; R2 = 0.313, p = Conclusion SPPB and chart review FRS are potential predictors of waitlist and transplant status in heart transplant candidates, whereas SPPB and FFP were associated with mortality. Research in a larger cohort is ongoing.