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Primary graft dysfunction (PGD) is a difficult to predict complication that continues to cause significant morbidity including chronic lung allograft dysfunction (CLAD). Understanding the mechanism behind PGD can aid in development of tools for risk stratification and possible intervention to improve outcomes. The Th2 immune response has been shown to counteract tissue-damaging inflammation to promote tissue homeostasis accelerating wound repair. We hypothesized that Th2 cytokines in peripheral blood, possibly as an indirect measure of immunologic imprinting from underlying advanced lung disease, could predict protection from PGD. Utilizing pretransplant samples from the multicenter Clinical Trials in Organ Transplantation (CTOT-20) study, we evaluated Th2 cytokines IL-4, IL-5, IL-6, IL-9, IL-10, IL-13, and MDC in 211 patients who subsequently underwent lung transplantation. PGD grading was assigned based on ISHLT guidelines. The association between Th2 cytokines and PGD was evaluated using bivariate logistic regression based on presence or absence of grade 2 or 3 PGD at 72 hours after transplant. Cytokine values were evaluated on a continuous basis. Median age of our cohort was 59 years old, of which 87% had a bilateral lung transplant, 49% had restrictive disease and 28% obstructive lung disease. 32% experienced grade 2 or 3 PGD within 72 hours post-transplant. Levels in peripheral blood of Th2 cytokines IL-4 (OR 0.07, p=0.043), IL-9 (OR 0.65, p=0.019), IL-13 (OR 0.67, p=0.023), and IL-6 (OR 0.71, p=0.036) pre-transplant were significantly associated with freedom from PGD. IL-5, IL -10, and MDC did not demonstrate significant associations with PGD. A higher pretransplant Th2 immune response may have a protective effect against lung injury as Th2 cytokines were associated with decreased incidence of higher grade PGD. The identification of both IL-4 and IL-13 may reflect a shared IL-4 receptor for these cytokines. These findings suggest the importance of the recipients' immunologic state prior to transplantation. In combination with other risk factors for PGD, pre transplant cytokine assessments could risk stratify recipients and aid in donor selection to prevent ischemia reperfusion injury. Understanding the mechanism of PGD development may lead to strategies to prevent the sequelae of allograft injury and CLAD after transplantation. [ABSTRACT FROM AUTHOR]

CMV infects over half the global population but can be life-threatening in lung transplant recipients. CMV infection is associated with reduced graft survival and chronic immune activation. We hypothesized that effective immune responses to CMV would be associated with improved post-transplant outcomes. This study enrolled 41 lung transplant recipients with CMV viremia. Patients were sampled pre- and post-onset of CMV viremia. We performed flow cytometry of PBMC, focusing on T cells. We generated single cell surface protein and transcriptomic profiles of CD8 T cells by CITE-seq. Differences in T cells were compared by linear regression and CLAD-free survival was assessed by Cox Proportional Hazards models. CMV viremia led to expansion of three distinct populations of terminally differentiated effector memory (TEMRA) CD8: CD57+KLRG1+, CD57−KLRG1+, and CD57+KLRG1− (Fig1A). Visualization of these populations by t-SNE suggested the CD57+ cells were more terminally differentiated (Fig1B). Increased frequency of CD57+KLRG1+ cells prior to CMV viremia was associated with effective clearance of virus in the periphery (Fig1C). A higher frequency of CD57+KLRG1+ cells conferred 3.8-fold reduced risk for CLAD or death (p = 0.015), while increased risk was observed in recipients with higher CD57−KLRG1+ (HR = 4.2, p = 0.025) and CD57+KLRG1− cells (HR = 2.4, p = 0.143) (Fig1D). CITE-seq analysis showed increased cytotoxic potential and effector function in CD57+KLRG1+ cells, CD57−KLRG1+ cells showed early evidence of exhaustion (Fig1E). CMV-expanded, phenotypically heterogeneous CD8 TEMRA were differentially associated with control of CMV viremia and CLAD onset. Favorable post-transplant outcomes may be improved by effective CMV-specific CD8 T cell responses. Understanding how these distinct CD8 TEMRA populations regulate CMV reactivation and control will be vital in efforts to prevent CMV-associated graft injury in lung transplantation. [ABSTRACT FROM AUTHOR]

As the population ages, the number of older adults assessed for heart transplant candidacy is notably increasing. However, it is not clear how best to assess risk beyond chronological age for this population. Our study focuses on the use of a biopsychosocial, chart-based frailty assessment in comparison with physical frailty assessments to attempt to predict clinical outcomes for heart transplant patients. 175 patients undergoing heart transplant evaluation were eligible for this single center observational study. Assessments were performed on all patients aged 55 years or older as well as in selected younger patients with clinical concern for frailty raised by the treating team. We conducted four frailty assessments: Short Physical Performance Battery (SPPB), Fried Frailty Phenotype (FFP), a 20-item Frailty Index (FI20), and Frailty Risk Score (FRS). In this study, FFP was weakly correlated with FRS (p=0.001, r2=0.224) while SPPB did not correlate with FRS (p=0.066, R2=0.075). None of the frailty assessments correlated with age. Pre-transplant frailty measured by SPPB was associated with failure to undergo transplant (p=0.035), but not by FFP or FRS. FRS was associated with 6-month readmission after transplant (p=0.029) while SPPB and FFP were not. SPPB and FFP were associated with mortality (p=0.022, p=0.008 respectively) while FRS was not (Figure). Chart review-based frailty assessments show potential prognostic value for older heart transplant candidates. These frailty assessments may be less time-consuming, virtual alternatives to physical frailty assessments that must be done in-person. In addition, chart-review frailty assessments have different associations with clinical outcomes, such as mortality, compared with physical frailty assessments. Future work should incorporate these measures into prognostic models and consider interventions for patients identified as frail, such as prehabilitation. [ABSTRACT FROM AUTHOR]

Age is a major risk factor for severe coronavirus disease 2019 (COVID-19), yet the mechanisms behind this relationship have remained incompletely understood. To address this, we evaluated the impact of aging on host immune response in the blood and the upper airway, as well as the nasal microbiome in a prospective, multicenter cohort of 1031 vaccine-naïve patients hospitalized for COVID-19 between 18 and 96 years old. We performed mass cytometry, serum protein profiling, anti-severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) antibody assays, and blood and nasal transcriptomics. We found that older age correlated with increased SARS-CoV-2 viral abundance upon hospital admission, delayed viral clearance, and increased type I interferon gene expression in both the blood and upper airway. We also observed age-dependent up-regulation of innate immune signaling pathways and down-regulation of adaptive immune signaling pathways. Older adults had lower naïve T and B cell populations and higher monocyte populations. Over time, older adults demonstrated a sustained induction of pro-inflammatory genes and serum chemokines compared with younger individuals, suggesting an age-dependent impairment in inflammation resolution. Transcriptional and protein biomarkers of disease severity differed with age, with the oldest adults exhibiting greater expression of pro-inflammatory genes and proteins in severe disease. Together, our study finds that aging is associated with impaired viral clearance, dysregulated immune signaling, and persistent and potentially pathologic activation of pro-inflammatory genes and proteins.

Post-acute sequelae of SARS-CoV-2 (PASC) is a significant public health concern. We describe Patient Reported Outcomes (PROs) on 590 participants prospectively assessed from hospital admission for COVID-19 through one year after discharge. Modeling identified 4 PRO clusters based on reported deficits (minimal, physical, mental/cognitive, and multidomain), supporting heterogenous clinical presentations in PASC, with sub-phenotypes associated with female sex and distinctive comorbidities. During the acute phase of disease, a higher respiratory SARS-CoV-2 viral burden and lower Receptor Binding Domain and Spike antibody titers were associated with both the physical predominant and the multidomain deficit clusters. A lower frequency of circulating B lymphocytes by mass cytometry (CyTOF) was observed in the multidomain deficit cluster. Circulating fibroblast growth factor 21 (FGF21) was significantly elevated in the mental/cognitive predominant and the multidomain clusters. Future efforts to link PASC to acute anti-viral host responses may help to better target treatment and prevention of PASC., (© 2024. The Author(s).)

Background: Evaluating organ suitability for transplantation based on infection risk is a core competency in transplant infectious disease (TID). It is unclear if trainees have opportunities to practice during training. We created a simulation curriculum to develop and evaluate this skill among infectious disease (ID) trainees., Methods: We created six simulation questions about organ suitability for transplant based on infection risk. During trainees' TID rotations, faculty texted or paged the simulation cases posing as the transplant coordinator. Trainees had 15 min to ask questions before deciding the suitability of the organ and explained their clinical reasoning in a survey. Trainees completed a post-simulation survey to evaluate its effectiveness., Results: ID trainees, including residents and fellows on rotation, from seven centers participated. Eighty-seven percent (13/15) of trainees felt the simulation was effective in teaching them this concept, and 80% (12/15) felt prepared for clinical practice. The proportion of correct responses was generally high among the six different cases (43%-100%); correct responses increased for some cases in the post-activity survey. Of the 100 clinical reasoning decisions made during the activity, 19% were discordant, where the trainee correctly identified suitable organs for incorrect reasons., Conclusion: Our simulation was effective in teaching when to accept or reject an organ for transplant and was a valuable educational tool. By evaluating clinical reasoning for decisions our simulation provides educators with nuanced insight and allows for targeted coaching. This study demonstrates a critical need for further educational tools in TID., (© 2023 Wiley Periodicals LLC.)

Introduction: An increasing number of older patients are undergoing evaluation for kidney transplantation; however, older patients experience increased rates of complications compared with younger patients, leading to the study of frailty assessments. Although many centers have evaluated the Fried Frailty Phenotype (FFP), less is known about the ability of the Short Performance Physical Battery (SPPB) to predict outcomes., Methods: Frailty assessment by FFP and SPPB was introduced into routine outpatient evaluation for patients aged 55 years and older referred for transplantation. Transplant rate, length of stay, readmission up to 3 months posttransplant, and death were reviewed. Patients were evaluated in an initial cohort followed by a validation cohort by FFP and SPPB. Multivariate analysis correcting for demographic characteristics was applied., Results: Patient cohorts reflected the racial and ethnic diversity of our population, including approximately 40% Hispanic patients. The first cohort of 514 patients demonstrated a significant association between frailty as measured by SPPB and transplantation (odds ratio [OR], 2.27; 95% CI, 1.38-3.83; p = .002). The second cohort of 1408 patients validated the association between frailty measured by SPPB and transplantation (OR, 2.81; 95% CI, 1.83-4.48; p < .001). In addition, there was a significant association between nonfrail status measured by SPPB and death (OR, 0.16; 95% CI, 0.04-0.62; p = .006)., Conclusions: Frailty assessment is a potentially useful approach for the assessment of transplant candidates. Our real-world study examined the performance of 2 methods of frailty evaluation methods in a diverse population, demonstrating that SPPB but not FFP was predictive of clinical outcomes. Incorporation of frailty assessments into transplant evaluation may improve risk stratification and optimize outcomes for older patients., Competing Interests: Declaration of Competing Interest All the authors declare no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: The use of vaccination to prevent infection has a long history, starting in the 1700s with Jenner. New innovations have led to improvements in the safety and efficacy of vaccines, from live attenuated viruses to subunit vaccines, to RNA-based vaccination for SARS-CoV-2. Despite this progress, however, solid organ transplant (SOT) recipients on immunosuppression demonstrate an impaired vaccine response compared with healthy controls. This issue is important given the increased vulnerability to infection in immunocompromised patients, especially in the setting of the Coronavirus Disease 2019 (COVID-19) pandemic., Methods: We reviewed the literature on key topics in vaccination with significant clinical impact on SOT patients., Results: Prior to COVID-19, a large amount of data has been published demonstrating impaired humoral and T-cell responses to multiple vaccinations targeting influenza, hepatitis B, VZV, and Pneumococcus. Poor immunogenicity can be addressed through the use of adjuvants to boost the immune response, even in the setting of senescence related to age or immunosuppression. New vaccines provide hope for preventing infection due to hepatitis C and Cytomegalovirus, and to the emerging infection, monkeypox. The data on the impact of the COVID-19 vaccine in SOT patients is reviewed, with a focus on seroconversion, antibody titer, and antigen-specific T cells. Factors associated with impaired response, including mycophenolate, are described., Conclusion: The history of vaccination demonstrates how scientific breakthroughs can be applied to clinical challenges. New approaches using adjuvants, strategic antigen selection, and RNA-based vaccines offer the potential to improve immune response in SOT recipients. Future innovations are needed to better protect the vulnerable immunocompromised host., (© 2023 Wiley Periodicals LLC.)