Infection in renal transplant recipients

Renal transplant recipients are susceptible to infection by a wide array of pathogens. Impaired inflammatory responses due to immunosuppressive therapies suppress clinical and radiologic findings engendered by microbial invasion. As a result, patients are often minimally symptomatic and evaluation and diagnosis are delayed. Specific microbiologic diagnosis is essential both for the optimization of antimicrobial therapy and to avoid unnecessary drug toxicities. Differential diagnosis is guided by knowledge of organisms commonly involved in infection in immunocompromised hosts and understanding of the limitations of prophylactic strategies. The risk of infection in the organ transplant recipient is determined by the interaction between the individual's epidemiologic exposures and net state of immunosuppression. Epidemiology includes environmental exposures in the community and hospital, organisms derived from donor tissues and latent infections activated in the host during immune suppression. The net state of immune suppression is determined by the interaction of all factors contributing to infectious risk. Routine antimicrobial prophylaxis is aimed at common infections and unique risk factors in individual patient groups. This includes trimethoprim-sulfamethoxazole (for Pneumocystis, Toxoplasma, most Nocardia and Listeria, common urinary pathogens), perioperative (eg, anti-fungal prophylaxis for pancreas transplants), or antiviral (for herpesviruses in high risk recipients).     

Rotavirus in Organ Transplantation: Drug‐Virus‐Host Interactions

Although rotavirus is usually recognized as the most common etiology of diarrhea in young children, it can in fact cause severe diseases in organ transplantation recipients irrespective of pediatric or adult patients. This comprehensive literature analysis revealed 200 cases of rotavirus infection with 8 related deaths in the setting of organ transplantation been recorded. Based on published cohort studies, an average incidence of 3% (187 infections out of 6176 organ recipients) was estimated. Rotavirus infection often causes severe gastroenteritis complications and occasionally contributes to acute cellular rejection in these patients. Immunosuppressive agents, universally used after organ transplantation to prevent organ rejection, conceivably play an important role in such a severe pathogenesis. Interestingly, rotavirus can in turn affect the absorption and metabolism of particular immunosuppressive medications via several distinct mechanisms. Even though rotaviral enteritis is self‐limiting in general, infected transplantation patients are usually treated with intensive care, rehydration and replacement of nutrition, as well as applying preventive strategies. This article aims to properly assess the clinical impact of rotavirus infection in the setting of organ transplantation and to disseminate the interactions among the virus, host and immunosuppressive medications.     

Infections after organ transplantation and immune response

Organ transplantation has provided another chance of survival for end-stage organ failure patients. Yet, transplant rejection is still a main challenging factor. Immunosuppressive drugs have been used to avoid rejection and suppress the immune response against allografts. Thus, immunosuppressants increase the risk of infection in immunocompromised organ transplant recipients. The infection risk reflects the relationship between the nature and severity of immunosuppression and infectious diseases. Furthermore, immunosuppressants show an immunological impact on the genetics of innate and adaptive immune responses. This effect usually reactivates the post-transplant infection in the donor and recipient tissues since T-cell activation has a substantial role in allograft rejection. Meanwhile, different infections have been found to activate the T-cells into CD₄⁺ helper T-cell subset and CD₈⁺ cytotoxic T-lymphocyte that affect the infection and the allograft. Therefore, the best management and preventive strategies of immunosuppression, antimicrobial prophylaxis, and intensive medical care are required for successful organ transplantation. This review addresses the activation of immune responses against different infections in immunocompromised individuals after organ transplantation.     

Screening of deceased organ donors: no easy answers

Transmission of infection to recipients of solid organs is uncommon but well documented. Improved technologies for the diagnosis of infectious diseases suggest possible changes to paradigms used in the screening of organ donors to prevent disease transmission with transplantation. Available microbiologic assays, including molecular tests, are generally designed for use as diagnostic tools in individuals believed to have a specific infection based on clinical or epidemiological criteria. By contrast, these assays often lack the performance characteristics required for screening of deceased organ donors. This challenge is apparent with the analysis of assays for human T-cell lymphotropic virus-I and -II in low-risk populations. Changing epidemiologic patterns associated with the spread of novel pathogens or altered patterns of immigration will necessitate flexibility in the "list" of potential pathogens. Individual benefits from transplantation generally outweigh the risk of transmission of infection. However, this favorable experience will not obviate the need to continuously improve screening practices.     

Infections in organ transplantations

Since cyclosporin A was introduced clinically, transplantation of solid organ grafts, has become a routine therapy for untreatable endstage-diseases of various organs, such as kidney, liver, heart and lung. Nowadays the most frequent cause of mortality and severe morbidity in transplant recipients is not graft rejection but infection. During the first three postoperative months organ recipients are extremely endangered for infectious diseases. Patients receive high dosages of immunosuppressive therapy, because immunogenecity of the graft is rather high. In course of the following months the allograft is more and more accepted by the recipients immune system. Consecutively immunosuppression is reduced and the risk of infection is diminished. --During the first postoperative month bacterial infections commonly appear. Thereafter viral infections can be observed more frequently. Cytomegalovirus infections are very dangerous in CMV-seronegative recipients with a lethality up to 90%. So a CMV-cross-match between the donor and recipient has to be performed. Transplant recipients have to be operated in aseptic conditions, with perioperative antibiotic prophylaxis. Regular serological analysis from blood and urine specimen has to be done to control bacterial, fungal and viral status, as well as regular monitoring of immunosuppressive regimen.     

Urinary tract infections after renal transplantation

Up to now one of the major problems for successful organ transplantation has been the reaction of the immune system of the recipient against the donor organ. This could lead to acute and chronic rejection, and in cases of unsuccessful treatment to the loss of the transplant. In organ graft recipients, immunosuppressive agents are used to prevent or treat rejection episodes and to maintain graft function. Although there is an increasing number of immunosuppressive substances, the immunosuppressive therapy currently in use is relatively unspecific and targets many immunological functions. The net state of immunosuppression is a complex function determined by the interaction of a number of factors, the most important of these are the dose, duration and temporal sequence in which immunosuppressive drugs are employed. Any kind of immunosuppressive protocol is thus associated with an increased infection rate. This has an important socioecological impact, because frequent hospitalizations resulting from infectious complications are necessary, having an overall mortality rate of 3.5% within 2 weeks of admission. The most common cause of septicaemia is urinary tract infection. Frequent urinary tract infections are associated with the early onset of chronic rejection, suggesting a pathogenetic relationship between these two features. The occurrence of chronic rejection has led to reduced transplant survival. The prevention of urinary tract infections, or the early diagnosis and accurate treatment of urinary tract infections is important in renal transplant recipients.     

Management of opportunistic infections in solid-organ transplantation

Solid-organ transplantation is often the last alternative in many patients with end-stage organ disease. Although advances in immunosuppressive regimens, surgical techniques, organ preservation, and overall management of transplant recipients have improved graft and patient survival, infectious complications remain problematic. Bacterial, fungal, viral, and parasitic infections are implicated after transplantation depending on numerous factors, such as degree of immunosuppression, type of organ transplant, host factors, and period after transplantation. Proper prophylactic and treatment strategies are imperative in the face of chronic immunosuppression, nosocomial and community pathogens, emerging drug resistance, drug-drug interactions, and medication toxicities. This review summarizes the pathophysiology, incidence, prevention, and treatment strategies of common posttransplant infections.     

Management of infections due to nontuberculous mycobacteria in solid organ transplant recipients—Guidelines from the American Society of Transplantation Infectious Diseases Community of Practice

These updated guidelines from the American Society of Transplantation Infectious Diseases Community of Practice review the epidemiology, diagnosis, prevention, and management of nontuberculous mycobacterial infections in the pre‐ and post‐transplant period. NTM commonly cause one of five different clinical syndromes: pleuropulmonary disease, skin and soft tissue infection, osteoarticular infection, disseminated disease, including that caused by catheter‐associated infection, and lymphadenitis. Diagnosis of these infections can be challenging, particularly when they are isolated from nonsterile spaces, owing to their ubiquity in nature. Consequently, diagnosis of pulmonary infections with these pathogens requires fulfillment of microbiologic, radiographic, and clinical criteria to address this concern. A combination of culture and molecular diagnostic techniques is often required to make a species‐level identification. Treatment varies depending on the species isolated and is complex, owing to drug toxicities, need for long‐term multidrug regimens, and consideration of complex drug‐drug interactions between antimicrobials and immunosuppressive agents. Given these treatment challenges, efforts should be made in both the hospital and community settings to limit exposure to these pathogens to the extent feasible.     

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.     

Cytomegalovirus in solid organ transplant recipients—Guidelines of the American Society of Transplantation Infectious Diseases Community of Practice

Cytomegalovirus (CMV) is one of the most common opportunistic infections that affect the outcome of solid organ transplantation. This updated guideline from the American Society of Transplantation Infectious Diseases Community of Practice provides evidence‐based and expert recommendations for screening, diagnosis, prevention, and treatment of CMV in solid organ transplant recipients. CMV serology to detect immunoglobulin G remains as the standard method for pretransplant screening of donors and transplant candidates. Antiviral prophylaxis and preemptive therapy are the mainstays of CMV prevention. The lack of a widely applicable viral load threshold for diagnosis and preemptive therapy is highlighted, as a result of variability of CMV nucleic acid testing, even in the contemporary era when calibrators are standardized. Valganciclovir and intravenous ganciclovir remain as drugs of choice for CMV management. Strategies for managing drug‐resistant CMV infection are presented. There is an increasing use of CMV‐specific cell‐mediated immune assays to stratify the risk of CMV infection after solid organ transplantation, but their role in optimizing CMV prevention and treatment efforts has yet to be demonstrated. Specific issues related to pediatric transplant recipients are discussed.     

The use and value of procalcitonin in solid organ transplantation

Procalcitonin (PCT) has been increasingly used as a biomarker of bacterial infection and as a tool to guide antimicrobial therapy, especially in lower respiratory tract and bloodstream infections. Despite its increased use, data in patients with solid organ transplants are limited. Even without the presence of infection, PCT increases as a result of surgical procedures during transplantation, implantation of devices, and use of induction immunosuppressive therapy. The risk of infection is also higher in solid organ transplant recipients when compared to the general population. Monitoring PCT in the early post‐transplant period seems to be a promising method for early detection of infectious complications. It has been shown that elevated PCT levels after one wk of transplantation are correlated with infectious complications. PCT may be a useful adjunctive biomarker that may improve early identification and guide appropriate treatment of infection or rejection, with the potential to further improve clinical outcomes. The use of serial PCT measurements may be more reliable than single values. It is important to recognize which factors may lead to PCT increases in the post‐transplantation period, which in turn will help understand the kinetics and utility of this biomarker in this important patient population.     

Infections complicating solid organ transplantation

The requirements for immune suppression after solid organ transplantation increases the risk of infection with a myriad of organisms. There are many unique and evolving aspects of infection after solid organ transplantation. Advances in immunosuppressive therapy and improved protocols for infection prophylaxis have resulted in changes in the timing and clinical presentation of opportunistic infections. Vigilance in the diagnostic evaluation of suspected infection in the solid organ transplant recipient is essential. This article reviews the basic evaluation and treatment options for many of the infectious conditions peculiar to the immunosuppressed patient.     

Strategies for safe living following solid organ transplantation—Guidelines from the American Society of Transplantation Infectious Diseases Community of Practice

The present AST‐IDCOP guidelines update information on strategies for safe living after organ transplantation. While transplantation carries an increased risk for infection from the recipient's environment due to lifelong immunosuppression, the goal is for the recipient to be able to return to their home and live as normal a life as possible with a functioning graft. The current guideline provides updates to prior recommendations including additions on infections from water and food sources, exposures to animals, cannabis use as well as sexual exposures or those encountered with travel. Similar to the prior editions, many of the recommendations are based on good infection prevention standards, extrapolation from other immunocompromised hosts, and risks found from cases series in transplant patients. Enhanced education and attention to incorporating safe living strategies into daily life should help to accomplish successful transplant with recipients achieving a fulfilling life away from the hospital.     

Strategies to halt 2019 novel coronavirus (SARS‐CoV‐2) spread for organ transplantation programs at the Sichuan Academy of Medical Science and Sichuan Provincial People’s Hospital,China

During the 2019 novel coronavirus (SARS‐CoV‐2) outbreak in China (from January 24 to March 11, 2020), our center performed 16 organ transplants (10 kidney, 4 liver, and 2 lung transplants) harvested from deceased donors. Regarding the strategies to prevent infections of SARS‐CoV‐2, we implemented specific measures for the donor and recipient management, as well as prevention of hospital‐acquired infections. All 16 organ recipients had a favorable outcome without SARS‐CoV‐2 infection. Our approaches aiming to interrupt the spread of SARS‐CoV‐2 within the transplantation wards were successful, and allowed us to maintain the transplantation program for deceased liver, kidney, and lung organ recipients.     

The impact of the prevention strategies on the indirect effects of CMV infection in solid organ transplant recipients

Transplant recipients receiving immunosuppressive therapy are at increased risk of active cytomegalovirus (CMV) infection and disease. Without appropriate prophylaxis, as many as 80% of solid organ transplant recipients may experience CMV infection. In addition to the direct effects of CMV, infection may be associated with a range of indirect effects, including an increase in risk of other infections, as well as a higher incidence of rejection, graft loss and death. The indirect effects of CMV infection can vary depending on the transplanted organ. For example, CMV-infected kidney transplant recipients may be at increased risk of cardiovascular disease and diabetes, while CMV infection in liver transplant recipients may potentiate hepatitis C infection and increase the risk of post-transplant lymphoproliferative disease. Indirect effects result from a number of pathological processes, including immune modulation and immunosuppression, generation of cytotoxic, pro-inflammatory responses, and smooth muscle proliferation. Prophylactic treatment with antiviral medication can reduce the risk of CMV disease, thereby improving graft survival and overall outcomes, particularly in kidney and heart transplant recipients. Antiviral prophylaxis should be considered for all patients at risk of CMV infection after solid organ transplantation. In this paper we review the main indirect effects of CMV infection in solid organ transplant recipients, and the impact of CMV prophylaxis on these effects.     

Surgical site infections: Guidelines from the American Society of Transplantation Infectious Diseases Community of Practice

These guidelines from the Infectious Diseases Community of Practice of the American Society of Transplantation review the diagnosis, prevention, and management of post‐operative surgical site infections (SSIs) in solid organ transplantation. SSIs are a significant cause of morbidity and mortality in SOT recipients. Depending on the organ transplanted, SSIs occur in 3%‐53% of patients, with the highest rates observed in small bowel/multivisceral, liver, and pancreas transplant recipients. These infections are classified by increasing invasiveness as superficial incisional, deep incisional, or organ/space SSIs. The spectrum of organisms implicated in SSIs in SOT recipients is more diverse than the general population due to other important factors such as the underlying end‐stage organ failure, immunosuppression, prolonged hospitalizations, organ transportation/preservation, and previous exposures to antibiotics in donors and recipients that could predispose to infections with multidrug‐resistant organisms. In this guideline, we describe the epidemiology, clinical presentation, differential diagnosis, potential pathogens, and management. We also provide recommendations for the selection, dosing, and duration of peri‐operative antibiotic prophylaxis to minimize post‐operative SSIs.     

Donor-derived human herpesvirus 8 and development of Kaposi sarcoma among 6 recipients of organs from donors with high-risk sexual and substance use behavior

Kaposi sarcoma (KS) can develop following organ transplantation through reactivation of recipient human herpesvirus 8 (HHV-8) infection or through donor-derived HHV-8 transmission. We describe 6 cases of donor-derived HHV-8 infection and KS investigated from July 2018 to January 2020. Organs from 6 donors, retrospectively identified as HHV-8-positive, with a history of drug use disorder, were transplanted into 22 recipients. Four of 6 donors had risk factors for HHV-8 infection reported in donor history questionnaires. Fourteen of 22 organ recipients (64%) had evidence of posttransplant HHV-8 infection. Lung recipients were particularly susceptible to KS. Four of the 6 recipients who developed KS died from KS or associated complications. The US opioid crisis has resulted in an increasing number and proportion of organ donors with substance use disorder, and particularly injection drug use history, which may increase the risk of HHV-8 transmission to recipients. Better awareness of the risk of posttransplant KS for recipients of organs from donors with HHV-8 infection risk could be useful for recipient management. Testing donors and recipients for HHV-8 is currently challenging with no validated commercial serology kits available. Limited HHV-8 antibody testing is available through some US reference laboratories and the Centers for Disease Control and Prevention.     

Opportunistic infections in renal allograft recipients

Two major factors for successful organ transplantation are better control of rejection and better prevention and treatment of infections. In renal allograft recipients, immunosuppressive drug therapy is the major cause of immunocompromised status and occurrence of infections, which arise most commonly as a result of invasion by endogenous opportunists. It may also follow colonization by exogenous environmental organisms and via transfer of cytomegalovirus along with the transplanted kidney. The overall incidence of opportunistic infections varies from center to center; up to 15% of renal transplant recipients die of these infections. Clinical signs and symptoms of infection in immunocompromised patients may be concealed or imitated by the underlying disease, and a high index of clinical suspicion is vital. The unusual pathogens encountered in these patients demand thorough investigation. A total of 84 opportunistic infections encountered in renal allograft recipients during histopathologic and cytopathological evaluation of various specimens during the last 15 years is presented in this report. Invasive fungal infections were the most common pathogens, amounting to 55% of all infections. The dramatic increase in the diversity and number of opportunistic infections detected in these patients is not only due to an increasing population of susceptible individuals but also due to an improved recognition by advanced laboratory diagnostic techniques. The success of management of opportunistic infections depends on strong clinical suspicion, early diagnosis, and prompt treatment. The challenges of early diagnosis of opportunistic infections and prompt treatment are great; the rewards are even greater.     

Outcome of Transplantation Using Organs From Donors Infected or Colonized With Carbapenem‐Resistant Gram‐Negative Bacteria

Donor‐derived infections due to multidrug‐resistant bacteria are a growing problem in solid organ transplantation, and optimal management options are not clear. In a 2‐year period, 30/214 (14%) recipients received an organ from 18/170 (10.5%) deceased donors with infection or colonization caused by a carbapenem‐resistant gram‐negative bacteria that was unknown at the time of transplantation. Among them, 14/30 recipients (47%) received a transplant from a donor with bacteremia or with infection/colonization of the transplanted organ and were considered at high risk of donor‐derived infection transmission. The remaining 16/30 (53%) recipients received an organ from a nonbacteremic donor with colonization of a nontransplanted organ and were considered at low risk of infection transmission. Proven transmission occurred in 4 of the 14 high‐risk recipients because donor infection was either not recognized, underestimated, or not communicated. These recipients received late, short or inappropriate posttransplant antibiotic therapy. Transmission did not occur in high‐risk recipients who received appropriate and prompt antibiotic therapy for at least 7 days. The safe use of organs from donors with multidrug‐resistant bacteria requires intra‐ and inter‐institutional communication to allow appropriate management and prompt treatment of recipients in order to avoid transmission of infection.