Nontuberculous mycobacteria infection in solid organ transplant recipients

Although advances in surgical technique, drug-induced immunosuppression, and supportive medical therapy have led to improved survival and quality of live after solid organ transplantations, infections still represent a major threat for transplant recipients.     

Management of dyslipidemia in adult solid organ transplant recipients

Solid organ transplantation (SOT) has revolutionized treatment of end-stage disease. Improvements in the SOT continuum of care have unmasked a significant burden of cardiovascular disease, manifesting as a leading cause of morbidity and mortality. Although several risk factors for development of post-transplant cardiovascular disease exist, dyslipidemia remains one of the most frequent and modifiable risks. An important contributor to dyslipidemia in SOT recipients is the off-target metabolic effects of immunosuppressive medications, which may alter lipoproteins and their metabolism. Dyslipidemia management is paramount as lipid-lowering therapy with statins has demonstrated reductions in graft vasculopathy, decreased rejection rates, and improved survival. Several nonstatin medication options are available, but data supporting their benefit in the SOT population are minimal, typically extrapolated from studies in the general population. Further compounding dyslipidemia management is the complex interplay of drug interactions between lipid-lowering and immunosuppressant medications, which can result in serious toxicity and/or therapeutic failure.     

Severe infections in critically ill solid organ transplant recipients

BackgroundSevere infections are among the most common causes of death in immunocompromised patients admitted to the intensive care unit. The epidemiology, diagnosis and treatment of these infections has evolved in the last decade.AimsWe aim to provide a comprehensive review of these severe infections in this population.SourcesReview of the literature pertaining to severe infections in critically ill solid organ transplant recipients. PubMed and Embase databases were searched for documents published since database inception until November 2017.ContentThe epidemiology of severe infections has changed in the immunocompromised patients. This population is presenting to the intensive care unit with specific transplantation procedure–related infections, device-associated infections, a multitude of opportunistic viral infections, an increasing number of nosocomial infections and bacterial diseases with a more limited therapeutic armamentarium. Both molecular diagnostics and imaging techniques have had substantial progress in the last decade, which will, we hope, translate into faster and more precise diagnoses, as well as more optimal empirical treatment de-escalation.ImplicationsThe key clinical elements to improve the outcome of critically ill solid organ transplant recipients depend on the knowledge of geographic epidemiology, specific surgical procedures, net state of immunosuppression, hospital microbial ecology, aggressive diagnostic strategy and search for source control, rapid initiation of antimicrobials and minimization of iatrogenic immunosuppression.     

Cutaneous infections from viral sources in solid organ transplant recipients

Although there is an abundance of information on cutaneous malignancies in transplant recipients, information on cutaneous infections in solid organ transplant recipients is underrepresented in dermatologic and transplant literature. Our paper provides a comprehensive review of viral cutaneous infections within the solid organ transplant population. We compiled literature specific to the solid organ transplant population, reviewing cutaneous manifestations secondary to viral infections. Furthermore, we discuss the diagnosis and treatment of such infections. The following is a list of the viruses that we will discuss:

• -Human papillomavirus
• -Human herpesvirus type 1,2
• -Varicella-Zoster virus
• -Cytomegalovirus
• -Epstein-Barr virus
• -Human herpesvirus type 6 variant A
• -Human herpesvirus type 6 variant B
• -Human herpesvirus type 7
• -Human herpesvirus 8
• -Trichodysplasia spinulosa polyomavirus
• -Human polyomavirus 7
• -Merkel cell polyomavirus
• -Molluscum contagiosum

     

Reduced incidence of pneumonia in influenza-vaccinated solid organ transplant recipients with influenza disease

Whether influenza vaccination influences the severity of illness in cases of clinical failure in solid organ transplant (SOT) recipients receiving influenza vaccine has not been extensively studied. Our goal was to evaluate the frequency of influenza vaccination among SOT recipients with influenza disease and its impact on the illness severity during the 2010–2011 season. Adult SOT recipients with confirmed influenza infection were included from December 2010 to April 2011. Follow-up data were recorded and antibody titres were determined using a microneutralization assay. Sixty-four SOT recipients were included in the study, ten (15.6%) with severe disease, requiring admission to intensive care units, of whom four (6.3%) died. In all, 34 (53.1%) received the 2010–2011 seasonal influenza vaccine and 32 (50.0%) received the 2009-H1N1 pandemic vaccine, and none had detectable antibodies against influenza at the time of diagnosis of influenza infection. Twenty-three (67.6%) of the patients that received the vaccine required hospital admission and presented less dyspnoea (10, 29.4% versus 14 (50.0%), p 0.09) and pneumonia (8, 23.8% versus 15, 50.0%, p 0.03, relative risk 0.3, 95% CI 0.1-0.9) than unvaccinated patients, with relative risk reductions of 60% and 70%, respectively. Although influenza vaccination confers protection on SOT recipients against developing influenza pneumonia, the rate of clinical failure is still high. New strategies to improve influenza immunization are needed for this group of patients.     

Cytokine-targeted therapy for the management of solid organ transplant recipients

IntroductionThe number of solid organ transplants completed annually continues to trend upwards each year. Despite this, maintenance immunosuppression available on the market has remained relatively stagnant. Standard triple immunosuppression, composed typically of tacrolimus, mycophenolate, and steroids, lead to many side effects that limit the use of these medications. Tacrolimus, specifically, causes nephrotoxicity that can lead to renal dysfunction requiring a kidney transplant down the road. Alternative therapies for the management of immunosuppression need to be identified to try to mitigate these adverse effects.BodyCytokines are responsible for facilitating T cell differentiation and lead to the activation of inflammatory mediators that can contribute to graft damage and ultimately rejection. IL-4, IL-6, IL-12/23, and IL-15 are attractive targets for medications to try to ameliorate graft rejection. Various cytokine-targeted medications are currently available on the market for the treatment of inflammatory and autoimmune conditions such as rheumatoid arthritis, psoriatic arthritis, Crohn’s, and multiple sclerosis.ConclusionThis article reviews cytokine involvement in alloimmunity and the potential role cytokine-targeted therapy may play in prevention of allograft rejection in solid organ transplant recipients.     

Malignancies in organ transplant recipients

The development of cancer in organ transplant recipients is well known; depressed immunosurveillance induced by the use of immunosuppressive agents for prevention of rejection is a causative factor. The types of malignancies in renal transplant patients vary geographically and are influenced by the type of immunosuppressant used. In the present study in Japan, malignancies had developed in 2.6% of renal transplant recipients; the observed number/expected number ratio was 2.78. For the primary sites, the relative risk in Japan was quite different from that in Western countries, with a lower frequency of skin cancer, an absence of Kaposi's sarcoma and higher frequencies of renal and thyroid cancer in Japan. Epstein-Barr virus is an oncogenic virus causing lymphoproliferative disorders in immunocompromised hosts. In renal transplant recipients, who usually receive hemodialysis before transplantation, human T lymphotrophic virus (HTLV)-1 is also oncogenic and causes adult T-cell leukemia/lymphoma. The HTLV-1 in donor blood might be transmitted to transplant recipients via transfusion during hemodialysis. The epidemiology and characteristics of representative malignancies in transplant recipients are described, with a review of pertinent literature.     

Multidrug-resistant Enterobacterales infections in abdominal solid organ transplantation

BackgroundTransplant recipients are highly susceptible to multidrug-resistant (MDR) related infections. The lack of early appropriate antimicrobial treatment may contribute to the high mortality due to MDR-related infections in transplant recipients especially in case of metallo-β-lactamases.ObjectivesIn this review, we present the current state of knowledge concerning multidrug-resistant Gram negative bacilli's risk management in the care of solid-organ transplant recipients and suggest control strategies.SourcesWe searched for studies treating MDR g-negative bacilli related infections in the renal and hepatic transplant patient population. We included randomized and observational studies.ContentSolid-organ transplant is the best therapeutic option for patients diagnosed with end-stage organ disease. While the incidence of opportunistic infections is decreasing due to better prevention, the burden of “classical” infections related to MDR bacteria especially related to Gram-negative bacteria is constantly increasing.Over the last two decades, various MDR pathogens have emerged as a relevant cause of infection in this specific population associated with significant mortality. Several factors related to the management of transplant donor candidates and recipients increase the risk of MDR infections in transplant recipients. The awareness of this high susceptibility of transplant recipients to MDR-related infections challenges the choice of empirical therapy, while its appropriateness can only be validated a posteriori. Indeed, the lack of early appropriate antimicrobial treatment may contribute to the high mortality due to MDR-related infections in transplant recipients especially in case of metallo-β-lactamases.ImplicationsMultidrug-resistant Gram-negative bacteria are associated with high morbidity and mortality in solid organ transplant recipients. It seems important to identify patients at risk of colonization/MDR bacteria to evaluate strategies to limit the risk of secondary infections and to minimize the inappropriate use of broad-spectrum antibiotics.     

Finding the right time for weaning off immunosuppression in solid organ transplant recipients

Solid organ transplantation (SOT) requires lifelong immunosuppression (IS) to prevent rejection and graft loss. The currently adopted immunosuppressive protocols are numerous and are based on the administration of at least two molecules with diverse mechanisms of action. Owing to the fact that the majority of immunosuppressants act non-selectively, the immune system is normally oversuppressed, and as a result is less able to both defend the host against infection and to control the spread of malignant cells. Consequently, long-term IS is burdened by chronic toxicity, which may be highly invalidating and may significantly influence patient’s quality of life, compliance to treatment, overall success rate, and patient and graft survival. In an ideal scenario, SOT recipients should initially receive just enough IS to favor the onset of clinical operational tolerance (COT), a condition where the immune system of the host does not attack the graft in the absence of any immunosuppressant. COT has been documented after liver transplantation (LT) and renal transplantation (RT). First, COT was accidentally detected in patients who were nonadherent to treatment and who spontaneously decided to stop all IS without any medical guidance or surveillance. Later, it was described in recipients who required IS withdrawal following the occurrence of malignant diseases. Based on strikingly convincing experimental data, several tolerogenic protocols have recently been applied in patients but overall the results have been disappointing. The current literature demonstrates that COT can be safely achieved in stable LT recipients, with completely different strategies. Importantly, the onset of an episode of acute rejection during the attempt of IS withdrawal would not worsen the clinical outcome. On the contrary, COT remains a major challenge after RT because the onset of acute rejection will substantiate in graft loss. Currently, a major field of investigation aims to define markers of COT, which will allow the selection of individuals who are more prone to develop COT. Preliminary results in both RT and LT have just been announced; however, these markers will require validation in prospective studies.     

Finding the right time for weaning off immunosuppression in solid organ transplant recipients

Solid organ transplantation (SOT) requires lifelong immunosuppression (IS) to prevent rejection and graft loss. The currently adopted immunosuppressive protocols are numerous and are based on the administration of at least two molecules with diverse mechanisms of action. Owing to the fact that the majority of immunosuppressants act non-selectively, the immune system is normally oversuppressed, and as a result is less able to both defend the host against infection and to control the spread of malignant cells. Consequently, long-term IS is burdened by chronic toxicity, which may be highly invalidating and may significantly influence patient's quality of life, compliance to treatment, overall success rate, and patient and graft survival. In an ideal scenario, SOT recipients should initially receive just enough IS to favor the onset of clinical operational tolerance (COT), a condition where the immune system of the host does not attack the graft in the absence of any immunosuppressant. COT has been documented after liver transplantation (LT) and renal transplantation (RT). First, COT was accidentally detected in patients who were nonadherent to treatment and who spontaneously decided to stop all IS without any medical guidance or surveillance. Later, it was described in recipients who required IS withdrawal following the occurrence of malignant diseases. Based on strikingly convincing experimental data, several tolerogenic protocols have recently been applied in patients but overall the results have been disappointing. The current literature demonstrates that COT can be safely achieved in stable LT recipients, with completely different strategies. Importantly, the onset of an episode of acute rejection during the attempt of IS withdrawal would not worsen the clinical outcome. On the contrary, COT remains a major challenge after RT because the onset of acute rejection will substantiate in graft loss. Currently, a major field of investigation aims to define markers of COT, which will allow the selection of individuals who are more prone to develop COT. Preliminary results in both RT and LT have just been announced; however, these markers will require validation in prospective studies.     

Prophylaxis and treatment for invasive fungal infections in solid organ transplant recipients]

Solid organ transplantation is becoming increasingly common in Japan. Despite invasive fungal infections being less common than bacterial and viral infections, fungal infections still result in a higher mortality rate. Empiric and pre-emptive therapy plays an important role in management of invasive fungal infections, because successful treatment is difficult after a definite diagnosis of an invasive disease, especially invasive aspergillosis. Given this situation, to improve outcome, high risk patients need to be identified and antifungal prophylaxis is mandatory in preventing the development of the disease. However, antifungal prophylaxis for solid organ transplant recipients remains controversial. New antifungal agents might change the choice of fungal prevention and treatment.     

Fibronectin in immune responses in organ transplant recipients

The immune response to an organ allograft involves perpetuation of T cell infiltration and activation. Advances in understanding the mechanisms of T cell activation have placed particular emphasis on the interactions between the T-cell receptor and antigen presenting cells, with little reference to the fact that in vivo activation occurs in the physical context of extracellular matrix proteins (ECM). Indeed, the possibility that ECM proteins may have a determining role in lymphocyte adhesion and tissue localization and function is now becoming more appreciated in view of growing evidence indicating that integrins and other T cell antigens bind ECM components, with some of these components exerting synergistic effects on T-cell activation. This review focuses on the importance of interactions between lymphocytes and fibronectin, a prominent ECM component, for cell migration and function in organ allograft recipients. It explores novel therapeutic approaches based on the assumption that fibronectin represents an active element in the process of T cell activation in the immune cascade triggered by organ transplantation.     

Immune response to CMV in solid organ transplant recipients: current concepts and future directions

Despite advances in immunosuppression and antiviral therapy, CMV continues to be a significant opportunistic pathogen adversely affecting the outcome of solid organ transplantation (SOT) recipients. While a significant proportion of CMV disease is caused by reactivation of latent virus, the risk is highest among CMV donor+ and recipient- SOT patients. CMV is responsible for both direct (e.g., pneumonitis, colitis) and indirect (e.g., rejection, atherosclerosis) morbidity and mortality. Healthy CMV-seropositive individuals have a high frequency of CMV-specific CD4(+) and CD8(+) T cells that provide immune protection by limiting CMV reactivation and replication. Changes to the innate and adaptive immune system from immunosuppressive therapy following SOT contribute to CMV disease pathogenesis. CMV disease after SOT is associated with poorer outcomes, thus novel strategies to prevent it are an area of active research. In this article, we review the current state of knowledge on the immune response to CMV following SOT.     

Immune response to CMV in solid organ transplant recipients: current concepts and future directions

Despite advances in immunosuppression and antiviral therapy, CMV continues to be a significant opportunistic pathogen adversely affecting the outcome of solid organ transplantation (SOT) recipients. While a significant proportion of CMV disease is caused by reactivation of latent virus, the risk is highest among CMV donor+ and recipient- SOT patients. CMV is responsible for both direct (e.g., pneumonitis, colitis) and indirect (e.g., rejection, atherosclerosis) morbidity and mortality. Healthy CMV-seropositive individuals have a high frequency of CMV-specific CD4⁺ and CD8⁺ T cells that provide immune protection by limiting CMV reactivation and replication. Changes to the innate and adaptive immune system from immunosuppressive therapy following SOT contribute to CMV disease pathogenesis. CMV disease after SOT is associated with poorer outcomes, thus novel strategies to prevent it are an area of active research. In this article, we review the current state of knowledge on the immune response to CMV following SOT.