Cryptococcal disease in the solid organ transplant setting: review of clinical aspects with a discussion of asymptomatic cryptococcal antigenemia Purpose of review: Cryptococcal infections are an important cause of morbidity and mortality in solid organ transplant patients. Here, we review the microbiology, epidemiology, clinical course, treatment, and outcomes of Cryptococcus in solid organ transplant recipients.
Recent findings: We identify the unique findings in solid organ transplant patients when compared to other immunocompromised patients such as those with HIV. We also describe our experience and outcomes with regard to solid organ transplant patients who do not have positive fungal cultures, but cryptococcal antigen positivity and concern for cryptococcal disease.
Summary: Our review will highlight the importance of these new diagnostic techniques in those with Cryptococcus and solid organ transplant, which will be the subject of new research.
Clostridium difficile infection in solid organ transplant recipients Purpose of review: Clostridium difficile infection (CDI) is a major healthcare-associated infection that causes significant morbidity and an economic impact in the United States. In this review, we provide an overview of Clostridium difficile infection in solid organ transplant recipients with an emphasis on recent literature.
Recent findings: C. difficile in solid organ transplant population has unique risk factors. Fecal microbiota transplantation has shown favorable results in treatment of recurrent C. difficile in this population. Preliminary data from animal studies suggests excellent efficacy with immunization against C. difficile toxins.
Summary: Over the last decade, number of individuals receiving solid organ transplants has increased exponentially making peri-transplant complications a common occurrence.
C. difficile is a frequent cause of morbidity in solid organ transplant recipients. Early and accurate diagnosis of C. difficile requires a stepwise approach. Differentiating between asymptomatic carriage and infection is a diagnostic challenge. Microbial diversity is inversely proportional to risk of C. difficile infection. Antimicrobial stewardship programs help to retain microbial diversity in individuals susceptible to CDI. Recurrent or relapsing C. difficile infection require fecal microbiota transplantation for definitive cure.
BK virus as a mediator of graft dysfunction following kidney transplantation Purpose of review: BK virus is a significant risk factor for kidney allograft dysfunction and loss among renal transplant recipients. Currently, there is no proven effective treatment except for the reduction of immunosuppression. In this review, we discuss diagnostic challenges and current treatment options for BK in kidney transplant recipients.
Recent findings: Antiviral and antibiotic therapies have been employed for BK viraemia with variable efficacy. In addition, novel therapeutic regimens such as adoptive transfer of targeted T cells have been described as possible treatment options for recipients with BK nephropathy. BK can also be seen in the native kidneys of pancreas, heart, lung and liver transplant recipients, suggesting that BK screening measures should be employed to other solid organ transplant recipients.
Summary: Early screening for BK combined with reduction of immunosuppression remains the mainstay of treatment for BK viraemia. New therapeutic advances demonstrate promise in vitro; however, the in-vivo efficacy will be demonstrated by future studies.
Pneumonia after liver transplantation Purpose of review: Pneumonia occurs in 8–23% of patients after liver transplantation and contributes considerably to their morbidity and mortality. With the increasing acuity of liver transplantation patients in the current era, pneumonias, particularly ventilator-associated pneumonias, and multidrug-resistant pathogens, are of growing concern.
Recent findings: Postliver transplantation pneumonia cause varies with the timing of infection. In the early period (<1 month postliver transplantation), nosocomial pneumonias, including ventilator-associated pneumonias and multidrug-resistant species are most common. During the intermediate period (1–6 months postliver transplantation), opportunistic infections predominate as intensive immunosuppression persists. In the late period (>6 months postliver transplantation), community-acquired bacterial and viral pneumonias arise, as immunosuppression is reduced. Numerous risk factors have been implicated in postliver transplantation pneumonias. Prevention is aimed at reducing bacterial colonization, preventing aspiration events, and utilizing surveillance and targeted antibiotics. Novel studies have also shown reduced risk of infection with personalized immunosuppression regimens guided by an immune function assay.
Summary: The etiologic patterns, risk factors, and preventive measures for postliver transplantation pneumonia must be understood to minimize patient exposure to modifiable risks and optimize recipient status in the perioperative period. Prevention is multifaceted and may be enhanced by personalization of immune therapy based on predisposition to infection and graft rejection.
Strongyloides stercoralis in solid organ transplantation: early diagnosis gets the worm Purpose of review: Strongyloidiasis is a parasitic infection affecting millions of people worldwide. Complications of infection are strongly associated with alcoholism, immunosuppression, and organ transplantation. Delayed diagnosis results in hyperinfection syndrome and disseminated strongyloidiasis leading to mortality rates approaching 80%. Early detection, and prevention of infection and transmission are key to diminish this illness.
Recent findings: In this review, we cover the basic concepts in immunity, immunosuppression, and disorder necessary for understanding the infectious syndromes associated with Strongyloides stercoralis infection. Focused discussion on donor-derived transmission and recipient risk in solid organ transplantation is presented. Current methodology for diagnosis, screening algorithms, and treatment are also reviewed.
Summary: Strongyloidiasis complicated by hyperinfection and dissemination remains associated with a poor outcome. The poor outcome pleads for a high level of suspicion and aggressive treatment in at-risk patients. As the population of transplant patients continues to increase, the risk of infection also increases, compelling us to address this highly fatal infectious complication in solid organ transplantation (SOT). Here we review the pathology, immunology, diagnosis, and treatment of strongyloides infection in the immunosuppressed SOT population.
Cytomegalovirus in liver transplant recipients Purpose of review: Cytomegalovirus (CMV) is the most common opportunistic infection following solid-organ transplant and remains a cause of life-threatening disease and allograft rejection in liver transplant recipients. The purpose of this review is to highlight the current strategies in diagnosis and management of this disease in this vulnerable population.
Recent findings: Identification of high-risk individuals and aggressive treatment with antiviral agents, either via prophylaxis or by early initiation during active disease, has become the standard of care. Despite this, CMV continues to exert a significant effect, remaining a major cause of morbidity and mortality.
Summary: Given these findings, continuing efforts are underway to determine whether further therapy, vaccination, or alternative management strategies may improve outcomes in solid-organ transplant recipients. Until that time, however, aggressive monitoring of post-transplant patients for signs and symptoms of CMV infection is the best strategy to prevent solid-organ loss and death.
Hepatitis E viral infection in solid organ transplant patients Purpose of review: The purpose of this chapter is to review the literature published in the past 10 years with focus to the best literatures published since 2015 regarding chronic hepatitis E virus (HEV) infection in patients who received solid organ transplantation.
Recent findings: Diagnosis of this disease relies primarily on identification of HEV RNA in serum and more recently in stool as way of predicting relapse and guide therapy duration. Current management focuses primarily on primary prevention and supportive care, because additional research is needed to identify efficacious pharmacologic therapy, though use of ribavirin has shown promise in case series in treatment of some genotypes.
Summary: Infection with HEV is a rare but significant infection in organ transplant recipients. Though initially thought to be a primarily self-limiting infection, cases of chronic and persistent infection are increasing, being recognized both in developing and developed nations as a cause of cirrhosis, and, in some cases, of fulminant hepatic failure. Clinical manifestations of this infection, including evidence of hepatocellular liver injury, are mostly indistinguishable from alternative diagnoses.
Invasive fungal infections following liver transplantation Purpose of review: The review outlines the microbiology, presentation, prophylactic strategies, resistance patterns, and consequences of invasive fungal infections (IFIs) in orthotopic liver transplantation (OLT) recipients.
Recent findings: There has been an increase in the proportion of non-albicans Candida causing IFIs. The biomarkers galactomannan and β-D-glucan should not be routinely used in the diagnosis of IFIs in OLT recipients due to their limited accuracy. Echinocandins have emerged as noninferior to fluconazole and other prophylactic regimens. Their broad spectrum of activity and side-effect profile are appealing; however, the development of echinocandin resistance, especially in Candida glabrata has been highlighted as one of their limitations.
Summary: A significant decline in IFIs but an increase in IFIs caused by non-albicans Candida species has been observed in the model for end-stage liver disease era. Diagnostic tools remain limited. Studies continue to support antifungal prophylaxis individualized to recipient risk with echinocandins now established as an additional option for antifungal prophylaxis. The appropriate duration of antifungal prophylaxis remains ill-defined with some studies advocating targeted therapy based on clinical status and others more prolonged therapy beyond the historically common 4 weeks. However, prolonged therapy with echinocandins can result in resistance.
Autologous islet transplantation: challenges and lessons Purpose of review: Human islet isolation and autotransplantation [autologous islet transplant (AUTX)] is performed to prevent or ameliorate brittle diabetes after total pancreatectomy performed for benign disease. The success or failure of the transplant can be associated with a profound impact on the individual's quality of life and even survival. AUTX offers unique insights into the effects of pancreas quality, islet number, isolation technique and alternate site engraftment on transplant efficacy. Herein, we review islet isolation with a focus on potential pathways to further optimize the endocrine outcome of AUTX, and compare and contrast differences in islet processing for AUTX and allotransplantation (allogeneic islet transplant).
Recent findings: New knowledge of human islet biology and issues surrounding the engraftment process offer opportunities for innovative approaches toward optimizing islet cell transplantation.
Summary: Improving the rate and durability of insulin independence in the often-times marginal dose model of AUTX may provide new insight toward improving the efficiency and durability of single donor islet (allogeneic islet transplant).
Donors after circulatory death pancreas transplantation Purpose of review: The use of organs from donors after circulatory death (DCD) has become standard practice in solid organ transplantation of most abdominal organs and has been used successfully in some centres for pancreas transplantation. Nevertheless, concerns regarding poor graft outcomes and complications remain. This review aims to discuss the current state of DCD pancreas transplantation and the associated outcomes.
Recent findings: In many countries, whereas the number of donors after brainstem death (DBD) remains stable, the mean age and BMI have increased making these donors, previously considered to be low risk, now more marginal. Recent meta-analyses have confirmed previous single-centre and registry reports that graft and patient survival after DCD pancreas transplantation are comparable with outcomes using pancreases from DBD donors; DCD pancreas transplantation is now common practice in several countries in Europe, particularly the United Kingdom. Although there have been reports of higher thrombosis rates after DCD pancreas transplantation, the significance of this is difficult to judge as the impact has not been seen in overall graft survival.
Summary: Pancreas transplantation using DCD organs is well tolerated and feasible when other risk factors are minimized. Although there has been some evidence of an increased risk of thrombosis, this has not translated into a significant difference in graft survival.
Live donor kidney – PAK versus SPK: how to decide? Purpose of review: Patients with type 1 diabetes and end stage renal disease face a complex choice when considering the relative risks and benefits of kidney transplant alone with or without subsequent pancreas after kidney transplant (PAK) or simultaneous kidney pancreas transplant (SPK).
Recent findings: SPK is considered the optimal treatment regarding long-term patient survival, but when also faced with the option of living donor kidney transplant with the potential for PAK later, the ideal option is less clear.
Summary: This review summarizes the current literature regarding SPK, living donor kidney transplant alone, and PAK transplant outcomes and examines the relative risks of pre- and posttransplant variables that impact patient and graft survival to help inform this complex treatment decision.
Long-term diabetes complications after pancreas transplantation Purpose of review: The intention of this study is to summarize present knowledge about adverse effects of hyperglycemia in diabetes, and in this context review more recent data concerning the effects of pancreas transplantation on a wide range of diabetic complications.
Recent findings: Effective blood glucose control by insulin delays progression of microvascular complications and probably improves survival in type 1 diabetes. A successful pancreas transplantation combined with a kidney graft has recently been found to prevent diabetic kidney lesions, and registry data support improved long-term patient survival. Cardiovascular mortality was reduced in one study, even though coronary heart disease was not significantly altered. Advanced coronary lesions may be too advanced in these patients at baseline. However, with a successful single pancreas transplant, which is generally performed in patients with near-normal kidney function, pancreas transplantation may improve left ventricular function. Development of retinopathy and neuropathy is delayed with functioning pancreas grafts, and both quality of life and certain skin lesions may improve after pancreas transplantation.
Summary: In patients with type 1 diabetes, pancreas transplantation may improve cardiac outcomes and ameliorate diabetic lesions in the kidney transplant. Also quality of life, neuropathy, retinopathy, and healing of certain skin lesions may be improved.
Surgery of pancreas transplantation Purpose of review: The surgical techniques of pancreas transplantation have been evolving and significantly improved over time. This article discusses different current techniques and their modifications.
Recent finding: At this time, the most commonly used technique is systemic venous drainage (for venous outflow) and enteric drainage (for management of exocrine pancreatic secretions). However, new modifications of established techniques such as gastric or duodenal exocrine drainage and venous drainage to the inferior vena cava continue to be introduced.
Summary: This article provides a state-of the-art review of the most prevalent up-to-date surgical techniques as well as a synopsis of their specific risks and benefits. The article also provides the most current registry data regarding utilization of different surgical techniques in the United State and worldwide.
The impact of next-generation sequencing in immunogenetics: current status and future directions Purpose of review: Next-generation sequencing (NGS) has now been established, and widely recognized, to be the preferred choice for human leukocyte antigen (HLA) typing. This transformation is based upon the many scientific, operational and economic benefits this technology affords. In this report, we review the major advantages, existing limitations and significant promise derived from adopting this technology in immunogenetics.
Recent findings: Significant benefits have emerged from the usage of NGS in a relatively short period, whereby we realize that this technology not only helps addressing the technical and operational problems we have had with the legacy methods for HLA typing, but equally important, it also allows for creative applications in stem cell and organ transplantation, new ways to investigate associations of the major histocompatibility complex (MHC) with many diseases and enhance our understanding regarding the MHC and non-MHC genomic interactions. The emerging picture is one of significant benefits in the diagnostic sphere of immunogenetics and transplantation and one of interconnectivity, integrating the many biological pathways controlled and affected by this unique genomic region.
Summary: NGS has revolutionized the science and practice of immunogenetics. In this article, we identify the still unresolved issues, the current benefits to transplantation and the potential for dissecting the complexity of the MHC, one of the most fascinating regions of the human genome. Using current trends, an attempt is made to predict future directions and outcomes.
Becoming a chef in the human leukocyte antigen kitchen: interpretation and modification of human leukocyte antigen–antibody assays Purpose of review: Fluorescence-based human leukocyte antigen (HLA) antibody detection methods, including flow cytometric crossmatch and single antigen bead assays revolutionized HLA antibody identification and assessment of immunological risk in transplant candidates and patients. Nevertheless, these assays are not flawless and their interpretation can be complex. This review highlights the limitations of the single antigen bead and flow cytometric crossmatch assays and discusses protocol modifications and interpretive approaches to address these issues.
Recent findings: Several limitations of HLA antibody detection methods have been identified in recent years. Protocol variability, denatured epitopes, and interfering factors can all significantly impact the identification of clinically relevant HLA antibodies. A number of solutions to address these challenges have been developed. These include pretreatment of sera, method standardization, and protocol modifications. In addition, HLA epitope-based analysis approaches to improve interpretation of antibody test results have been introduced.
Summary: In the 50 years, since Patel and Terasaki first developed the crossmatch assay there have been remarkable advances in HLA antibody testing methodology. However, with these advances, new problems emerged and solutions had to be developed. As the technology continues to evolve, our methods and ability to interpret results must keep pace to provide transplant patients with the best possible care.
Histocompatibility and management of the highly sensitized kidney transplant candidate Purpose of review: Increasing national participation in kidney paired donation and implementation of new sharing policies via the current kidney allocation system have brought about greater opportunities for the most highly sensitized patients awaiting a kidney transplant. The purpose of this review is to discuss the application of histocompatibility data in the context of the clinical practice of kidney transplantation as pertains to the sensitized candidate.
Recent findings: With desensitization techniques, transplantation across virtually any antibody barrier is technically feasible, but long-term outcomes after transplantation are improved when the immunologic match between donor and recipient is optimized. Solid-phase immunoassays have changed the landscape of histocompatibility testing. These sensitive and specific assays for identifying donor-specific antibody not only help determine feasibility of transplantation but have enabled outcomes studies aimed at understanding the spectrum of risk posed by different antibody profiles. This, in turn, has helped guide decision-making in donor selection, in particular for sensitized patients.
Summary: Careful evaluation of donor-specific antibody profiles with individualized, patient-specific determination of unacceptable antigens is necessary to ensure that highly sensitized patients receive every opportunity for transplantation.
Application and interpretation of histocompatibility data in thoracic (heart and lung) transplantation Purpose of review: The purpose of the review is to update our current understanding and utilization of immunogenetic tools in heart and lung transplant.
Recent findings: Increasingly, complex patients have been managed perioperatively for heart and lung transplant using a variety of tests and techniques. Recent treatment regimens and listing strategies have exploited recent laboratory advances. However, the better characterization has led to an even more complex description of sensitized heart and lung candidates. Several recent studies have examined antibody strengths and behavior to guide clinical decision-making and examine postoperative outcomes. Finally, non-human leukocyte antigen antibodies have emerged as possible determinants of allograft outcome in heart and lung transplant.
Summary: Heart and lung transplant candidates with preformed and de-novo posttransplant antibodies continue to represent a challenging and high-risk group of patients. Modern immunogenetic techniques have broadened our understanding and have revealed an even more complex relationship between antibodies, allografts, and outcomes.
Application and interpretation of histocompatibility data in pediatric kidney transplantation Purpose of review: Advances in technology to assess immunologic risk in solid organ transplant offer an opportunity to optimize the approach to pediatric deceased donor kidney transplant in the setting of a new allocation system in the United States.
Recent findings: Degree of human leukocyte antigen (HLA) mismatch, class II HLA mismatch, unacceptable antigens and donor-specific antibody (DSA) detected by solid-phase assays, and epitope matching pretransplant affect pediatric kidney transplant outcomes. Detection of de novo DSAs (dnDSAs) posttransplant has been associated with increased risk of acute rejection and worse allograft function. Development of dnDSA occurs in recipients with greater epitope mismatching.
Summary: Improved long-term outcomes may be anticipated in pediatric kidney transplant recipients by incorporating extended HLA mismatch information and updating the clinical approach to donor kidney matching using available technology to identify clinically relevant immunologic risk.
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