Transplant-associated Infections Research Articles

Consensus Definitions of Cytomegalovirus (CMV) Infection and Disease in Transplant Patients Including Resistant and Refractory CMV for Use in Clinical Trials: 2024 Update From the Transplant Associated Virus Infections Forum.

Cytomegalovirus (CMV) infection and disease are important causes of morbidity and mortality in transplant recipients. For the purpose of developing consistent reporting of CMV outcomes in clinical trials, definitions of CMV infection and disease were developed and most recently published in 2017. Since then, there have been major developments, including registration of new antiviral agents. Therefore, the Transplant Associated Virus Infections Forum, which consists of scientists, clinicians, regulators, and industry representatives, has produced an updated version of these definitions that incorporates recent knowledge with the aim of supporting clinical research and drug development. This also includes an update regarding the definition of resistant and refractory CMV infections previously published in 2019. As the field evolves, the need for updates of these definitions is clear, and collaborative efforts among clinicians, scientists, regulators, and industry representatives can provide a platform for this work.

Examining the impact of immunosuppressive drugs on antibody-dependent cellular cytotoxicity (ADCC) of human peripheral blood natural killer (NK) cells and gamma delta (γδ) T cells

BackgroundHuman natural killer (NK) cells and gamma delta (γδ) T cells may impact outcomes of solid organ transplantation (SOT) such as lung transplantation (LTx) following the differential engagement of an array of activating and inhibitory receptors. Amongst these, CD16 may be particularly important due to its capacity to bind IgG to trigger antibody-dependent cellular cytotoxicity (ADCC) and the production of proinflammatory cytokines. While the use of immunosuppressive drugs (ISDs) is an integral component of SOT practice, their relative impact on various immune cells, especially γδT cells and CD16-induced functional responses, is still unclear. MethodsThe ADCC responses of peripheral blood NK cells and γδT cells from both healthy blood donors and adult lung transplant recipients (LTRs) were assessed by flow cytometry. Specifically, the degranulation response, as reflected in the expression of CD107a, and the capacity of both NK cells and γδT cells to produce IFN-γ and TNF-α was assessed following rituximab (RTX)-induced activation. Additionally, the effect of cyclosporine A (CsA), tacrolimus (TAC), prednisolone (Prdl) and azathioprine (AZA) at the concentration of 1 ng/ml, 10 ng/ml, 100 ng/ml, and 1000 ng/ml on these responses was also compared in both cell types. ResultsFlow cytometric analyses of CD16 expresion showed that its expression on γδT cells was both at lower levels and more variable than that on peripheral blood NK cells. Nevertheless functional analyses showed that despite these differences, γδT cells like NK cells can be readily activated by engagement with RTX to degranulate and produce cytokines such as IFNg and TNF-a. RTX-induced degranulation by either NK cells or γδT cells from healthy donors was not impacted by co-culture with individual ISDs. However, CsA and TAC but not Prdl and AZA did inhibit the production of IFN-γ and TNF-α by both cell types. Flow cytometric analyses of RTX-induced activation of NK cells and γδT cells from LTRs suggested their capacity to degranulate was not markedly impacted by transplantation with similar levels of cells expressing CD107 pre- and post-LTx. However an impairment in the ability of NK cells to produce cytokines was observed in samples obtained post LTx whereas γδT cell cytokine responses were not significantly impacted. ConclusionsIn conclusion, the findings show that despite differences in the expression levels of CD16, γδT cells like NK cells can be readily activated by engagement with RTX and that in vitro exposure to CsA and TAC (calcineurin inhibitors) had a measurable effect on cytokine production but not degranulation by both NK cells and gdT cells from healthy donors. Finally the observation that in PBMC obtained from LTx recipients, NK cells but not γδT cells exhibited impaired cytokine reponses suggests that transplantation or chronic exposure to ISDs differentially impacts their potential to respond to the introduction of an allograft and/or transplant-associated infections.

Transplant associated infections-The role of the gastrointestinal microbiota and potential therapeutic options.

Infectious complications are common following kidney transplantation and rank in the top five causes of death in patients with allograft function. Over the last 5 years, there has been emerging evidence that changes in the gastrointestinal microbiota following kidney transplantation may play a key role in the pathogenesis of transplant-associated infections. Different factors have emerged which may disrupt the interaction between the gastrointestinal microbiota and the immune system, which may lead to infective complications in kidney transplant recipients. Over the last 5 years, there has been emerging evidence that changes in the gastrointestinal microbiota following kidney transplantation may play a key role in the pathogenesis of transplant-associated infections. This review will discuss the structure and function of the gastrointestinal microbiota, the changes that occur in the gastrointestinal microbiota following kidney transplantation and the factors underpinning these changes, how these changes may lead to transplant-associated infectious complications and potential treatments which may be instituted to mitigate this risk.

Monitoring for Viral Infections in Transplant Patients

Monitoring of transplant patients for viral infections allows individualized treatment regimens based on the risk for severe viral disease and quantification of viral loads in patient samples. Depending on the transplant type (solid-organ versus hematopoietic stem cell transplant), donor/recipient serostatus, degree of immunosuppression, and time from transplant, a variety of strategies can be used to manage the risk of post-transplant viral infections. They include empiric suppressive therapy, viral load monitoring, and diagnostic testing algorithms. Since the majority of transplant-associated viral infections are due to reactivation of latent infection, monitoring for viremia can allow early detection and initiation of antiviral therapy or a decrease of immunosuppressive medication in an attempt to limit progression to severe disease. Viral load tests using quantitative-PCR methods are a standard method for monitoring viremia, allowing early detection and tracking of viral infections in this immunocompromised patient population, yet there is limited standardization of testing methods between laboratories.

The swiss transplant cohort study: lessons from the first 6years.

Prospective cohort studies significantly contribute to answering specific research questions in a defined population. Since 2008, the Swiss Transplant Cohort Study (STCS) systematically enrolled >95% of all transplant recipients in Switzerland, collecting predefined data at determined time points. Designed as an open cohort, the STCS has included >3900 patients to date, with a median follow-up of 2.96years (IQR 1.44-4.73). This review highlights some relevant findings in the field of transplant-associated infections gained by the STCS so far. Three key general aspects have crystallized: (i) Well-run cohort studies are a powerful tool to conduct genetic studies, which are crucially dependent on a meticulously described phenotype. (ii) Long-term real-life observations are adding a distinct layer of information that cannot be obtained during randomized studies. (iii) The systemic collection of data, close interdisciplinary collaboration, and continuous analysis of some key outcome data such as infectious diseases endpoints can improve patient care.

Comparison of In Vitro Susceptibility Characteristics of Candida Species from Cases of Invasive Candidiasis in Solid Organ and Stem Cell Transplant Recipients: Transplant-Associated Infections Surveillance Network (TRANSNET), 2001 to 2006

Invasive fungal infections (IFI) are a major cause of morbidity and mortality among both solid organ transplant (SOT) and hematopoietic stem cell transplant (HSCT) recipients. Candida is the most common cause of IFI in SOT recipients and the second most common cause of IFI in HSCT recipients. We determined susceptibilities to fluconazole, voriconazole, itraconazole, posaconazole, amphotericin B, and caspofungin for 383 invasive Candida sp. isolates from SOT and HSCT recipients enrolled in the Transplant-Associated Infection Surveillance Network and correlated these results to clinical data. Fluconazole resistance in C. albicans, C. tropicalis, and C. parapsilosis isolates was low (1%), but the high percentage of C. glabrata and C. krusei isolates within this group of patients increased the overall percentage of fluconazole resistance to 16%. Voriconazole resistance was 3% overall but was 8% among C. glabrata isolates. On multivariable analysis, among HSCT recipients fluconazole nonsusceptibility was independently associated with C. glabrata, non-Hodgkin's lymphoma, cytomegalovirus (CMV) antigenemia, diabetes active at the time of the IFI, and any prior amphotericin B use; among SOT recipients, fluconazole nonsusceptibility was independently associated with any fluconazole use in the 3 months prior to the IFI, C. glabrata, ganciclovir use in the 3 months prior to the IFI, diabetes acquired since the transplant, and gender.

Prospective Surveillance for Invasive Fungal Infections in Hematopoietic Stem Cell Transplant Recipients, 2001–2006: Overview of the Transplant‐Associated Infection Surveillance Network (TRANSNET) Database

The incidence and epidemiology of invasive fungal infections (IFIs), a leading cause of death among hematopoeitic stem cell transplant (HSCT) recipients, are derived mainly from single-institution retrospective studies. The Transplant Associated Infections Surveillance Network, a network of 23 US transplant centers, prospectively enrolled HSCT recipients with proven and probable IFIs occurring between March 2001 and March 2006. We collected denominator data on all HSCTs preformed at each site and clinical, diagnostic, and outcome information for each IFI case. To estimate trends in IFI, we calculated the 12-month cumulative incidence among 9 sequential subcohorts. We identified 983 IFIs among 875 HSCT recipients. The median age of the patients was 49 years; 60% were male. Invasive aspergillosis (43%), invasive candidiasis (28%), and zygomycosis (8%) were the most common IFIs. Fifty-nine percent and 61% of IFIs were recognized within 60 days of neutropenia and graft-versus-host disease, respectively. Median onset of candidiasis and aspergillosis after HSCT was 61 days and 99 days, respectively. Within a cohort of 16,200 HSCT recipients who received their first transplants between March 2001 and September 2005 and were followed up through March 2006, we identified 718 IFIs in 639 persons. Twelve-month cumulative incidences, based on the first IFI, were 7.7 cases per 100 transplants for matched unrelated allogeneic, 8.1 cases per 100 transplants for mismatched-related allogeneic, 5.8 cases per 100 transplants for matched-related allogeneic, and 1.2 cases per 100 transplants for autologous HSCT. In this national prospective surveillance study of IFIs in HSCT recipients, the cumulative incidence was highest for aspergillosis, followed by candidiasis. Understanding the epidemiologic trends and burden of IFIs may lead to improved management strategies and study design.

Introduction: Infection in Solid Organ Transplant Recipients

Infectious disease after transplantation remains a field in evolution. Improved immunosuppressive therapies for organ transplantation have reduced the incidence of allograft rejection while increasing susceptibility to opportunistic infections and virally mediated malignancies. Traditional patterns of opportunistic infection after transplantation have also been altered by the emergence of organisms with antimicrobial resistance and by antifungal (including Pneumocystis) and antiviral prophylaxis (i.e. for cytomegalovirus [CMV] and other herpesviruses) (1). Improved microbiologic diagnostic tools (e.g. nucleic acid testing) are used in the routine management of common infections (e.g. CMV, Epstein-Barr virus [EBV]) and have allowed the definition of new clinical syndromes (e.g. BK polyomavirus nephropathy) and of donor-derived infections (e.g. due to lymphocytic choriomeningitis virus [LCMV]). At the same time, a variety of newer techniques are available, largely on a research basis (e.g. HLA-linked tetramer binding, intracellular cytokine staining) to assess pathogen-specific immunity. These may be used to investigate the recipient’s susceptibility to specific infections and are increasingly entering clinical practice. In the past decade, Transplant infectious disease has emerged as an integral subspecialty component of most successful transplant programs.

American Society of Transplantation Recommendations for Screening, Monitoring and Reporting of Infectious Complications in Immunosuppression Trials in Recipients of Organ Transplantation

In recent years, major progress has been made in the development, investigation and clinical application of novel immunosuppressive drug therapies to prevent acute rejection. Critical to the ultimate clinical application of new drug therapies is the ongoing performance of large multi-center clinical trials. However, there has been a paucity of infectious disease monitoring built into these protocols. Given that infectious complications are a major source of morbidity and mortality in transplant recipients, the assessment of the magnitude of risk of infection associated with a given immunosuppressive strategy may be as important as the assessment of rejection. For the above reasons, screening, monitoring and reporting recommendations for common transplant-associated infections were developed for use in clinical trials evaluating immunosuppressive strategies. These recommendations have two major goals: (i) to provide clinically relevant definitions for tracking infectious complications occurring in participants in immunosuppressive trials and (ii) where appropriate, to recommend specific laboratory monitoring and surveillance methods.