A case controlled study of risk factors for metastatic squamous cell carcinoma in organ transplant recipients: single academic medical center.

Solid organ transplant recipients (SOTRs) are at high risk of cutaneous squamous cell carcinoma (cSCC) metastasis. Despite prior studies identifying risk factors, mortality remains high. Understanding additional risk factors may aid in reducing mortality in this population. This study aimed to investigate risk factors and predictive variables for metastatic cSCC in SOTRs. The primary goal was to accurately identify transplant patients at increased risk of metastatic cSCC. A retrospective case-control study in a single institution of 3576 cases of organ transplants were identified from January 1991 to July 2022. A cohort of metastatic cancer patients and two randomly generated age and organ matched control cohorts were identified. 16 SOTR patients developed metastatic cSCC. The majority were male, with high-risk tumor sites. Tumor depth varied and half exhibited perineural invasion. Cylex® (p = 0.05) and white blood cell counts (p = 0.04) were significantly lower in these patients compared to control. Lung transplants were at highest risk relative to other solid organ transplants. Voriconazole exposure was also associated with increased metastatic risk (p = 0.04). Small sample size at a single institution. Close monitoring of SOTR, especially those with lung transplants given their increased risk, reducing immunosuppression, and limiting exposure to voriconazole can improve outcomes in SOTRs with metastatic cSCC.

Identification of HIV infection in two solid organ recipients three years after transplantation / Identificación de infección por el virus de la inmunodeficiencia humana en dos receptores de órgano sólido tres años después del trasplante

Routine screening of organ donors to detect human immunodeficiency virus (HIV) infection has detected the rare transmission of the virus through organ transplantation. However, despite routine screening, HIV transmission remains a risk in organ transplantation since, unlike tissues, solid organs cannot be processed, disinfected, or modified to inactivate infectious pathogens. A case of possible transmission of HIV by organ transplant is described below, from a previously seronegative donor to two recipients.

El examen de rutina de los donantes de órganos para detectar la infección por el virus de la inmunodeficiencia humana (HIV) ha hecho que la transmisión del virus mediante el trasplante de órganos sea poco común. Sin embargo, a pesar de las pruebas de detección de rutina, la transmisión del HIV continúa siendo un riesgo del trasplante de órganos ya que, a diferencia de los tejidos, los órganos sólidos no se pueden procesar, desinfectar, ni modificar para inactivar patógenos infecciosos. A continuación, se describe un caso de posible transmisión de HIV por trasplante de órganos de un donante previamente seronegativo a dos de sus receptores.

Current Perspectives on Letermovir and Maribavir for the Management of Cytomegalovirus Infection in Solid Organ Transplant Recipients.

Cytomegalovirus (CMV) infection is arguably the most important infectious complication that negatively affects the outcome of solid organ transplantation. For decades, CMV management after transplantation has relied on antiviral drugs that inhibit viral DNA polymerase (ganciclovir, foscarnet, and cidofovir). However, their use has been complicated by myelosuppression, nephrotoxicity, and selection of drug-resistant viruses. During the past few years, the therapeutic armamentarium for the management of CMV in solid organ transplant recipients has expanded with the approval of letermovir for CMV prophylaxis in high-risk CMV D+/R- kidney recipients, and maribavir for the treatment of refractory and resistant CMV infection. Both drugs offer significant improvement when compared to standard anti-CMV therapies; letermovir was as efficacious for CMV prevention, whereas maribavir was more effective in treating refractory and resistant CMV infections. Both letermovir and maribavir have favorable safety profiles compared to CMV DNA polymerase inhibitors, without the risk of neutropenia and leukopenia associated with ganciclovir and renal toxicities associated with foscarnet and cidofovir. Moreover, letermovir and maribavir are orally bioavailable, which allows convenient outpatient treatment. However, letermovir and maribavir have a significant drug interaction potential in solid organ transplant recipients, resulting in higher levels of calcineurin inhibitors (cyclosporine and tacrolimus) and mTOR inhibitors (sirolimus and everolimus). Both letermovir and maribavir are CMV-specific and do not have clinical efficacy against other herpes viruses. Thus, there is a need for additional antiviral drugs to prevent herpes simplex and other herpes viruses when clinically indicated. This article provides a comprehensive review of the clinical data supporting the use of letermovir and maribavir in clinical practice. The author provides perspectives on the role of these newly approved drugs in the current management landscape of CMV infection in solid organ transplantation.

Mechanistic Understanding of EBV+Lymphoproliferative Disease Development After Transplantation.

Posttransplant lymphoproliferative disorders (PTLDs) are among the most common malignant complications after transplantation, leading to a drastic reduction in patient survival rates. The majority of PTLDs are tightly linked to Epstein-Barr virus (EBV+PTLDs) and are the result of an uncontrolled proliferation of EBV-infected cells. However, although EBV infections are a common finding in transplant recipients, most patients with high EBV loads will never develop EBV+PTLD. Natural killer cells and EBV-specific CD8+ T lymphocytes are critical for controlling EBV-infected cells, and the impairment of these cytotoxic immune responses facilitates the unfettered proliferation of EBV-infected cells. Recent years have seen a considerable increase in available literature aiming to describe novel risk factors associated with the development of EBV+PTLD, which may critically relate to the strength of EBV-specific natural killer cell and EBV-CD8+ T lymphocyte responses. The accumulation of risk factors and the increased risk of developing EBV+PTLD go hand in hand. On the one hand, most of these risk factors, such as the level of immunosuppression or the EBV donor and recipient serologic mismatch, and distinct genetic risk factors are host related and affect cytotoxic EBV-specific immune responses. On the other hand, there is growing evidence that distinct EBV variants may have an increased malignant potential and are thus more likely to induce EBV+PTLD. Here, we aim to review, from a mechanistic point of view, the risk factors for EBV+PTLD in the host and the infecting EBV variants that may explain why only a minority of transplant recipients develop EBV+PTLD.

Immune Control of Human Cytomegalovirus (HCMV) Infection in HCMV-Seropositive Solid Organ Transplant Recipients: The Predictive Role of Different Immunological Assays.

Human cytomegalovirus (HCMV) infection remains a major complication for solid organ transplant recipients (SOTRs). The aim of this study was to evaluate the role of HCMV-specific T cell immunity measured at the time of the HCMV-DNA peak in predicting the spontaneous clearance of infection. The performance of cytokine flow cytometry using infected dendritic cells (CFC-iDC), infected cell lysate (CFC-iCL) and pp65 peptide pool (CFC-pp65 pool) as stimuli, as well as ELISPOT assays using infected cell lysate (ELISPOT-iCL) and the pp65 peptide pool (ELISPOT-pp65 pool), was analysed. Among the 40 SOTRs enrolled, 16 patients (40%) required antiviral treatment for an HCMV infection (Non-Controllers), while the others spontaneously cleared the infection (Controllers). At the HCMV-DNA peak, the number of HCMV-specific CD4+ T cells detected by the CFC-iDC, CFC-iCL and CFC-pp65 pool assays in Controllers was higher than that detected in Non-Controllers, while no difference was observed in terms of HCMV-specific CD8+ T cell response. The same trend was observed when the HCMV-specific T cell response was measured by ELISPOT-iCL and ELISPOT-pp65 pool. We observed that the CD4+ CFC-pp65 pool assay was the best predictor of self-resolving HCMV infection at the time of the HCVM-DNA peak. The CFC-pp65 pool assay is able to discriminate between CD4+ and CD8+ T cell responses and could be used in daily clinical practice.

TLR4 signalling in ischemia/reperfusion injury: a promising target for linking inflammation, oxidative stress and programmed cell death to improve organ transplantation outcomes.

Transplantations represent the principal therapeutic interventions for terminal organ failure, a procedure that has salvaged myriad lives annually. Ischemia/reperfusion injury (IRI) is frequently correlated with an unfavourable prognosis and is relevant for early graft dysfunction and graft survival. IRI constitutes a complex pathological state influenced by a series of factors such as oxidative stress, metabolic stress, leukocytic infiltration, programmed cell death pathways, and inflammatory immune responses. Reducing ischemia/reperfusion injury is one of the main directions of transplantation research. Toll-like receptors (TLRs) are important pattern-recognition receptors expressed on various organs that orchestrate the immune responses upon recognising PAMPs and DAMPs. Targeting the TLR4 signalling has recently been suggested as a promising approach for alleviating IRI by affecting inflammation, oxidative stress and programmed cell death (PCD). In this minireview, we summarise the role of TLR4 signalling in regulating inflammation, oxidative stress and PCD in organ transplantation and discuss their interactions during IRI. A detailed understanding of the multiple functions of TLR4 in IRI provides novel insights into developing therapies to improve organ transplantation outcomes.

Risk Factors and Outcomes Associated With the Development of Persistent Acute Kidney Injury in Non-Renal Solid Organ Transplant Recipients: Systematic Review and Meta-Analysis.

Persistent acute kidney injury (pAKI), compared with acute kidney injury (AKI) that resolves in <72 h, is associated with worse prognosis in critically ill patients. Definitions and prognosis of pAKI are not well characterized in solid organ transplant patients. Our aims were to investigate (a) definitions and incidence of pAKI; (b) association with clinical outcomes; and (c) risk factors for pAKI among heart, lung, and liver transplant recipients. We systematically reviewed the literature including PubMed, Embase, Web of Science, and Cochrane from inception to 8/1/2023 for human prospective and retrospective studies reporting on the development of pAKI in heart, lung, or liver transplant recipients. We assessed heterogeneity using Cochran's Q and I2. We identified 25 studies including 6330 patients. AKI (8%-71.6%) and pAKI (2.7%-55.1%) varied widely. Definitions of pAKI included 48-72 h (six studies), 7 days (three studies), 14 days (four studies), or more (12 studies). Risk factors included age, body mass index (BMI), diabetes, preoperative chronic kidney disease (CKD), intraoperative vasopressor use, and intraoperative circulatory support. pAKI was associated with new onset of CKD (odds ratio [OR] 1.41-11.2), graft dysfunction (OR 1.81-8.51), and long-term mortality (OR 3.01-13.96), although significant heterogeneity limited certainty of CKD and graft dysfunction outcome analyses. pAKI is common and is associated with worse mortality among liver and lung transplant recipients. Standardization of the nomenclature of AKI will be important in future studies (PROSPERO CRD42022371952).

Causality between herpes virus infections and allograft dysfunction after tissue and organ transplantation: a two-sample bidirectional Mendelian randomization study.

Background: Observational studies have suggested that herpes virus infections increase the risk of allograft dysfunction after tissue and organ transplantation, but it is still unclear whether this association is causal. The aim of this study was to assess the causal relationship between four herpes virus infections and allograft dysfunction. Methods: We used two-sample bidirectional Mendelian randomization (MR) to investigate the causality between four herpes virus infections - cytomegalovirus (CMV), Epstein-Barr virus (EBV), herpes simplex virus (HSV) and varicella zoster virus (VZV) - and allograft dysfunction after tissue and organ transplantation. Based on summary data extracted from genome-wide association studies (GWAS), we chose eligible single nucleotide polymorphisms (SNPs) as instrumental variables. The Inverse variance weighted (IVW) method was used as the main analysis method, supplemented by Weighted median and MR-Egger analyses. The MR-PRESSO test, MR-Egger intercept test, heterogeneity test, leave-one-out analysis and funnel plot were used to analyze the sensitivity of MR results. Results: We found EBV early antigen-D (EA-D) antibody levels and shingles were the only two variables associated with an increased risk of allograft dysfunction. No evidence of allograft dysfunction increasing the risk of the four herpes virus infections was observed. Sensitivity analyses confirmed the robustness of our results. Conclusions: Our results suggest that EBV and VZV are involved in graft rejection or dysfunction. However, the relationship between CMV and HSV infections and allograft dysfunction remains unclear and requires further clarification.

Ehrlichiosis and anaplasmosis in solid organ transplantation: A case series and review of the literature.

Ehrlichiosis and anaplasmosis are rising tickborne infections posing significant risks to solid-organ transplant (SOT) patients. We present three cases highlighting clinical presentations, diagnostic challenges, and the benefits of microbial cell-free DNA (mcfDNA) sequencing. Emphasizing early diagnosis and preventive measures, we advocate for advanced diagnostic modalities to improve outcomes in this vulnerable population.

The use of digital health interventions to deliver prehabilitation in solid organ transplant recipients: are we there yet?

PURPOSE OF REVIEW: Prehabilitation, defined as preparing the body physically and psychologically for upcoming surgery is of increasing prominence in presurgical care. The aim of this review is to discuss the evidence base around prehabilitation in solid organ transplantation, the use of digital health as a tool to deliver these interventions, and consider future directions. RECENT FINDINGS: Prehabilitation is of increasing interest as an adjunct to pretransplant care for individuals working up for solid organ transplantation. To date, research has shown that prehabilitation is acceptable and feasible; however, the literature base remains small. The majority of research has been delivered using in-person rehabilitation programmes, and the evidence base utilizing digital health as a means to deliver prehabilitation is limited. SUMMARY: To date, the research evidence base in prehabilitation for solid organ transplantation is limited. Evidence in other surgical populations has demonstrated promising results, particularly in aerobic capacity, physical function and postoperative complications. Further high-quality randomized controlled clinical trials are required to strengthen the evidence base, understand how digital health can be harnessed and utilized to deliver multimodal prehabilitation with an aim to see how this may form part of routine care in the solid organ transplantation pathway.

Cytomegalovirus Retinitis in the Modern Era of Solid Organ Transplantation.

BACKGROUND: Cytomegalovirus retinitis (CMVR) is a well-described complication of CMV disease in immunocompromised hosts. While robust data exists for CMVR in patients with acquired immunodeficiency syndrome (AIDS), the incidence and risk factors for CMVR in solid organ transplant recipients (SOTR) with CMV viremia are less defined. METHODS: We performed a retrospective cohort study of SOTR who had CMV viremia and underwent routine ophthalmologic examination between 1/1/2018 and 3/16/2022. Univariate statistics were performed to evaluate risk factors for development of CMVR. RESULTS: Overall, 38 patients were included, primarily kidney (78.9%), heart (7.9%), and liver (7.9%) transplant recipients. Five patients (13.2%) developed CMVR during the study period. CMVR was diagnosed an average 281 days after index transplantation, 84 days from the most recent rejection episode, and 69 days from onset of viremia. Only 1 patient (20%) had symptoms at the time of CMVR diagnosis. CMVR was associated with preceding allograft rejection as well as transplanted organ type. CONCLUSION: While CMV tissue disease more commonly manifests in other organs, CMVR occurred relatively frequently in this group of high-risk SOTR with CMV viremia. As most of the patients in our study did not have ocular symptoms at the time of diagnosis, routine ophthalmologic screening should be considered in SOTR with CMV viremia.

Risk Factors and Outcomes of Mucorales Infection in a Modern Cohort of Solid Organ Transplant, Hematopoietic Cell Transplant, and Chimeric Antigen Receptor T-cell Therapy Recipients.

BACKGROUND: Mucorales infections continue to cause significant morbidity and mortality in immunocompromised hosts despite the advent of new approaches for diagnosis and treatment of fungal infections. We aimed to evaluate risk factors and outcomes of Mucorales infection in solid organ transplant, hematopoietic cell transplant, and chimeric antigen receptor T-cell therapy recipients. METHODS: This single-center retrospective study included solid organ transplant, hematopoietic cell transplant, and chimeric antigen receptor T-cell patients with cultures positive for Mucorales. RESULTS: Forty-three patients were included for analysis; 34 solid organ transplant (79%) and 9 hematopoietic stem cell transplant or chimeric antigen receptor T-cell (21%). Infection with Mucorales occurred a median of 184 days after transplant. At the time of diagnosis, 36 patients were on antifungal prophylaxis with the majority receiving posaconazole (53%). Thirty-three had clinically significant disease; 30 received definitive anti-Mucorales therapy and 3 empiric antifungal therapy. Isavuconazole was the most common azole used for treatment in monotherapy recipients. All-cause mortality was 64% and, of these deaths, 18 (75%) were directly related to Mucormycosis. The highest mortality was seen in disseminated and intra-abdominal disease (100%), followed by pulmonary disease (50%). There was no significant association with mortality and transplant type or number of immunosuppressive agents. CONCLUSION: Mucormycosis is an important cause of morbidity and mortality in immunocompromised patients. Breakthrough infection was not uncommon in this study. Data regarding the incidence of infection at approximately 6 months after transplantation can inform prophylaxis and treatment regimens. The spectrum of antifungal regimens used reflects the lack of consensus on ideal regimens for these organisms and a need for more studies.

Clinical Impact of Community-Acquired Respiratory Viruses in Patients With Solid Organ Transplants.

BACKGROUND: Community-acquired respiratory viruses (CARVs) are associated with poor outcome in solid organ transplant recipients. We reviewed some of these outcomes such as respiratory support, length of stay, admission to the intensive care unit, steroid use, and 30-day all-cause mortality. METHODS: Multihospital, single center, retrospective review of electronic health records from January 1, 2014, to December 31, 2019. RESULTS: Twenty-three solid organ transplant recipients (20 male and 3 female) who tested positive for CARVs were identified. The mean age at admission was 60 years, average length of stay was 8 days with 2 patients needing >2 weeks. Six patients required intensive care unit and 8 required supplemental oxygen support. CARV distribution was rhinovirus in 48%, parainfluenza in 29%, metapneumovirus in 12%, respiratory syncytial virus in 0.03%, adenovirus in 0.03%, and non-novel coronavirus in 0.06%. All patients were immunosuppressed, intravenous immunoglobulins were used in 3 patients, antivirals in 7 patients (ribavirin in 6 and oseltamivir in 1), and steroids in 10 patients. Twelve patients had transplant organ biopsy with 5 showing acute cellular rejection. Thirty-five percent of patients died within 1 year (2 during the same admission). CONCLUSION: Transplant recipients are at a high risk of infections, especially CARVs, which may increase morbidity and mortality. In our observational study, we assessed patients with solid organ transplants who were admitted and tested positive for CARVs, and the associated impact on their clinical course. Careful analysis of the results will help us to emphasize the importance of timely diagnosis and treatment in specific populations.

Adverse Pregnancy Outcomes in Solid Organ Transplant Recipients: A Systematic Review and Meta-Analysis.

Importance: Transplant recipients experience high rates of adverse pregnancy outcomes; however, contemporary estimates of the association between solid organ transplantation and adverse pregnancy outcomes are lacking. Objective: To evaluate the association between solid organ transplantation and adverse pregnancy outcomes and to quantify the incidence of allograft rejection and allograft loss during pregnancy. Data Sources: PubMed/MEDLINE, EMBASE and Scopus databases were searched from January 1, 2000, to June 20, 2024, and reference lists were manually reviewed. Study Selection: Cohort and case-control studies that reported at least 1 adverse pregnancy outcome in pregnant women with solid organ transplantation vs without solid organ transplant or studies that reported allograft outcomes in pregnant women with solid organ transplantation were included following independent dual review of abstracts and full-text articles. Data Extraction and Synthesis: Two investigators abstracted data and independently appraised risk of bias using the Newcastle Ottawa Scale. A random-effects model was used to calculate overall pooled estimates using the DerSimonian-Laird estimator. Reporting followed the Meta-analysis of Observational Studies in Epidemiology (MOOSE) reporting guideline. Main Outcomes and Measures: Primary pregnancy outcomes were preeclampsia, preterm birth (<37 weeks), and low birth weight (<2500 g). Secondary pregnancy outcomes were live birth rate, gestation, very preterm birth (<32 weeks), very low birth weight (<1500 g), and cesarean delivery. Allograft outcomes were allograft loss and rejection during pregnancy. Results: Data from 22 studies and 93 565 343 pregnancies (4786 pregnancies in solid organ transplant recipients) were included; 14 studies reported adverse pregnancy outcomes, and 13 studies provided data for allograft outcomes. Pregnancies in organ transplant recipients were associated with significantly increased risk of preeclampsia (adjusted odds ratio [aOR], 5.83 [95% CI, 3.45-9.87]; I2 = 77.4%), preterm birth (aOR, 6.65 [95% CI, 4.09-12.83]; I2 = 81.8%), and low birth weight (aOR, 6.51 [95% CI, 2.85-14.88]; I2 = 90.6%). The incidence of acute allograft rejection was 2.39% (95% CI, 1.20%-3.96%; I2 = 68.5%), and the incidence of allograft loss during pregnancy was 1.55% (95% CI, 0.05%-4.44%; I2 = 69.2%). Conclusions and Relevance: In this systematic review and meta-analysis, pregnancies in recipients of a solid organ transplant were associated with a 4 to 6 times increased risk of preeclampsia, preterm birth, and low birth weight during pregnancy. There was a low overall risk of graft rejection or loss during pregnancy.

Immune response against bacterial infection in organ transplant recipients.

This comprehensive review delves into the intricate dynamics between the immune system and bacterial infections in organ transplant recipients. Its primary objective is to fill existing knowledge gaps while critically assessing the strengths and weaknesses of current research. The paper accentuates the delicate balance that must be struck between preventing graft rejection through immunosuppression and maintaining robust immunity against bacterial threats. In this context, personalized medicine emerges as a transformative concept, offering the potential to revolutionize clinical outcomes by tailoring immunosuppressive regimens and vaccination strategies to the unique profiles of transplant recipients. By emphasizing the pivotal role of continuous monitoring, the review underscores the necessity for vigilant surveillance of transplant recipients to detect bacterial infections and associated immune responses early, thereby reducing the risk of severe infections and ultimately improving patient outcomes. Furthermore, the study highlights the significance of the host microbiome in shaping immune responses, suggesting that interventions targeting the microbiome hold promise for enhancing bacterial immunity in transplant recipients, both in research and clinical practice. In terms of future research directions, the review advocates for large-scale, longitudinal studies encompassing diverse patient cohorts to provide more comprehensive insights into post-transplant immune responses. It also advocates integrating multi-omics approaches, including genomics, transcriptomics, proteomics, and microbiome data, to understand immune responses and their underlying mechanisms. In conclusion, this review significantly enriches our understanding of immune responses in transplant recipients. It paves the way for more effective and personalized approaches to managing infections in this complex setting.

The pre-transplant evaluation: Considerations for trainees and early career transplant infectious diseases clinician.

Transplant infectious disease (TID) clinicians are integral to the pre-transplantation evaluation. Pre-transplant evaluations allow clinicians to assess risk factors for latent infections and relevant exposures to potential pathogens, address immunizations, and optimize patients' health and understanding of life after transplant. However, there is not a standardized approach to the pre-transplant evaluation. This article reviews the details of performing successful pre-transplant evaluations, including updated recommendations on available vaccines and contemporary opinions on marijuana use. This resource can be used for teaching with trainees or for early career TID clinicians.

Emerging shadows: HHV-8-associated encephalitis unveiled in a solid organ transplant recipient.

Human herpesviruses (HHVs) cause a wide variety of central nervous system (CNS) infections including meningitis and encephalitis. While HHV-8 is not typically associated with neurological diseases, several studies have indicated a relationship, such as secondary central nervous system (CNS) metastases and a few isolated cases of HHV-8 encephalitis in acquired immunodeficiency syndrome (HIV). However, it has not been previously linked to encephalitis in solid organ transplantation (SOT). This case presents the first-ever instance of HHV-8 encephalitis in a SOT recipient. Our case highlights the association of HHV-8-related diseases, such as post-transplant Kaposi's Sarcoma (KS), with encephalitis. The patient was diagnosed with KS before developing neurological symptoms and received a prompt clinical response through intravenous foscarnet and ganciclovir treatment for 14 days. It is important to note that HHV-8 is a rare cause of encephalitis, and diagnosis requires a high index of suspicion in the appropriate clinical context, allowing for the use of antiviral therapy. This case also underscores the importance of considering the possibility of HHV-8-related diseases in SOT recipients, as they are at risk of developing such infections.

Strongyloides stercoralis infection in solid organ transplant recipients.

PURPOSE OF REVIEW: Strongyloides stercoralis infection remains of concern due to its high associated morbidity among solid organ transplant recipients (SOTR) and the risk of donor-derived infection (DDI). We review key aspects of epidemiology to inform screening for and treatment of chronic infection among organ transplant candidates to reduce the risk of infectious complications in the posttransplant setting. RECENT FINDINGS: In this work, we offer guidance regarding the optimal management of Strongyloides hyperinfection syndrome and disseminated infection and offer recommendations regarding posttreatment surveillance and the potential need for repeat treatment during subsequent periods of augmented immunosuppression. This review also provides updated recommendations for screening of deceased and living donors as recently proposed by the Organ Procurement and Transplantation Network's Ad Hoc Disease Transmission Advisory Committee. SUMMARY: Risk reduction of Strongyloides infection in the SOTR population can be further enhanced by optimized treatment of infection, posttreatment surveillance during at-risk periods and recent proposed policy shifts to universal donor screening.