The case for cytomegalovirus prophylaxis in solid organ transplantation

Cytomegalovirus prevention strategies have been debated for the past decade. This review argues in favour of the prophylaxis strategy. Clinical trials comparing prophylaxis to pre-emptive therapy have, thus far, had insufficient power to differentiate strategies, especially with regard to the indirect effects of CMV. From meta-analyses, prospective trials, observational studies, and case control studies, there is evidence that prophylaxis prevents cytomegalovirus infection and disease, reduces the indirect effects of cytomegalovirus, including organ rejection and transplant associated, all cause mortality as well as opportunistic infection, and even bacteremia as well as post transplant lymphoproliferative disease. Prophylaxis has also been shown to be cost effective. One must recognise that with the current prophylaxis regimens employed for 3 months post-transplantation, late onset cases of cytomegalovirus disease may occur. Cytomegalovirus replication monitoring may be necessary after cessation of prophylaxis, especially in the high risk cytomegalovirus seropositive donor to cytomegalovirus seronegative recipient. Future trials with longer periods of prophylaxis are being undertaken.     

Inflammatory bowel disease following solid organ transplantation

Inflammatory bowel disease (IBD) is a T cell driven inflammatory condition of the gut. Following solid organ transplantation (SOT), de novo IBD has been reported despite anti-T cell therapy for the prevention of organ rejection. This paradox is illustrated with a case report, highlighting the difficult diagnostic criteria, the potential role of Damage or Pathogen Associated Molecular Pattern Molecules [DAMPs and PAMPs] that drives aspects of ongoing inflammation within the transplanted organ as well as the intestine, and the therapeutic strategies applied. Recurrent IBD is more common than de novo IBD following transplantation, with cumulative risks ten years after orthotopic liver transplantation of 70% and 30%, respectively. Furthermore, the annual incidence of de novo IBD following solid organ transplantation has been estimated to be 206 cases/100,000 or ten times the expected incidence of IBD in the general population (approximately 20 cases/100,000). The association of IBD with other autoimmune conditions such as primary sclerosing cholangitis and autoimmune hepatitis, both common indications for liver transplantation, may play a contributory role, particularly in view of the observation that IBD is more common following liver transplant than other solid organ transplants. Recurrent IBD following transplant appears to run a more aggressive course than de novo IBD, with a higher proportion requiring colectomy for medically refractory disease. Risk factors that have been associated with development of post-transplant IBD include acute CMV infection and the use of tacrolimus.     

Modulation of immune responses following solid organ transplantation by microRNA

Organ transplantation, an accepted treatment for end stage organ failure, is often complicated by allograft rejection and disease recurrence. In this review we will discuss the potential role of microRNAs in allograft immunity especially leading to rejection of the transplanted organ. microRNAs (miRNAs), originally identified in C. elegans, are short non-coding 21–24 nucleotide sequences that bind to its complementary sequences in functional messenger RNAs and inhibits post-translational processes through RNA duplex formation resulting in gene silencing (Lau et al., 2001). Gene specific translational silencing by miRNAs regulates pathways for immune responses such as development of innate immunity, inflammation, T-cell and B-cell differentiation and signaling that are implicated in various stages of allograft rejection. miRNAs also play a role in development of post-transplant complicacies like fibrosis, cirrhosis, carcinogenesis often leading to graft loss and poor patient outcome. Recent advancements in the methods for detecting and quantifying miRNA in tissue biopsies, as well as in serum and urine samples, has led to identification of specific miRNA signatures in patients with allograft rejection and have been utilized to predict allograft status and survival. Therefore, miRNAs play a significant role in post-transplant events including allograft rejection, disease recurrence and tumor development impacting patient outcome.     

Potential and limitations of regulatory T-cell therapy in solid organ transplantation

Over the past few years, the therapeutic potential of Treg has been highlighted in the field of autoimmune diseases and after allogeneic transplantation. The first hurdle for the therapeutic use of Treg is their insufficient numbers in non-manipulated individuals, in particular when facing strong immune activation and expanding effector cells, such as in response to an allograft. Here we review current approaches being explored for Treg expansion in the perspective of clinical therapeutic protocols. We describe different Treg subsets that could be suitable for clinical application, as well as discuss factors such as the required dose of Treg, their antigen-specificity and in vivo stability, that have to be considered for optimal Treg-based immunotherapy in transplantation. Since Treg may not be sufficient as stand-alone therapy for solid organ transplantation in humans, we draw attention to possible hurdles and combination therapy with immunomodulatory drugs that could possibly improve the in vivo efficacy of Treg.     

Aggressive natural killer-like T-cell malignancy with leukemic presentation following solid organ transplantation

NK-like T-cell malignancies are part of a spectrum of lymphoproliferative diseases that complicate immunosuppression associated with solid organ transplantation. We describe 2 patients with long-standing immunosuppression following solid organ transplantation. Both patients had systemic symptoms that included fever, myalgia, and weight loss. Organ involvement and lymphadenopathy were not initially observed. Unique to these 2 cases are the initial leukemic symptoms, which led to further characterization and identification of NK-like T-cell malignancies. Both patients exhibited an anomalous T/NK phenotype, CD56 positivity, and atypical blastic architecture of the large granular lymphocytes. Clonal rearrangement of T-cell receptor genes was detected in both patients. In 1 patient, a cytogenetic abnormality involving 8q24 was demonstrated. The disease course in both patients was aggressive, with involvement of multiple sites and rapid demise. This study emphasizes the importance of including NK-like T-cell malignancies in the differential diagnosis of lymphoproliferative disorders associated with immunosuppression and recognizing that an aggressive clinical course may follow leukemic presentation of disease.     

Comparison of different techniques for detection of cytomegalovirus infection following bone marrow transplantation

A total of 317 different clinical samples obtained from patients following bone marrow transplantation and 56 blood and urine samples from seronegative control persons were screened for the presence of human cytomegalovirus (CMV) using virus culture and slot-blot hybridization. Immunohistochemical techniques using monoclonal antibodies to various viral antigens and in situ hybridization techniques were also utilised for detection of CMV in tissue samples. In cell suspensions of blood, bone marrow and effusions, and in liver biopsies, CMV DNA could be demonstrated more often by slot-blot and in situ hybridization techniques than by virus culture or immunostaining of viral antigens. For detection of CMV in lung biopsies and other clinical samples containing mainly cell-free virus, such as urine, bronchial lavage and throat washings, virus culture was found to be at least as sensitive as the hybridization techniques. Immunostaining proved to be a fast and sensitive technique for detection of CMV in tissues and may thus provide additional information about viral replication and clinical relevance of the virus infection.     

Prophylaxis for CMV should now replace pre-emptive therapy in solid organ transplantation

Cytomegalovirus is a significant cause of morbidity and mortality in transplantation. Controversy exists concerning whether prophylactic or pre-emptive therapy is the optimal strategy for preventing CMV disease. In addition, CMV impacts the transplanted graft, transplant recipient and transplant programme beyond just causing CMV disease; thus questioning whether 'asymptomatic' CMV replication should also be prevented. In this Forum article, prophylactic therapy is advocated as the preferred approach for preventing CMV disease. Prophylactic therapy has a large body of supportive controlled clinical studies demonstrating its efficacy and cost effectiveness. In addition, prophylactic therapy has the benefit of preventing other herpes viruses and other opportunistic superinfections by reducing the immunosuppressive effects of CMV. Moreover, a small but growing body of information suggests that prophylactic therapy may also have a beneficial effect on organ outcomes, including rejection. In contrast, pre-emptive therapy is limited by its reliance on intensive surveillance, which presents logistical difficulties and requires perfect patient compliance. Ambiguity still exists concerning the best surveillance method and its effect on patient-care costs. Each proposed diagnostic approach has limitations, which are affected by the prevalence of CMV in the population studied, the particular assay employed, and the frequency of surveillance. The suggested benefits of pre-emptive therapy, such as decreased cost, fewer adverse medication effects and less antiviral resistance have not been adequately proven in head-to-head clinical studies. We therefore support the proposition that transplant patients at risk for any level of CMV replication will significantly benefit from effective antiviral prophylaxis.     

Indirect allorecognition in solid organ transplantation

Recipient T cell recognition of donor major histocompatibility complex (MHC) alloantigens plays a central role in both acute and chronic rejection of human organ allografts. Two different pathways of T cell recognition of donor MHC alloantigens have been described. The direct pathway involves T cell recognition of intact MHC molecules expressed by donor antigen-presenting cells (APCs). The second, or indirect pathway, operates via T helper cell recognition of peptides derived from the processing and presentation of allogeneic MHC molecules on self-APCs. At the onset of primary acute rejection, recipient CD4+ T cell responses to donor HLA-DR alloantigens are limited to a single dominant determinant present on one of the disparate alloantigens and restricted by one of the responder's HLA-DR molecules. In allograft recipients with recurring episodes of rejection, and/or at the onset of chronic rejection, recipient T cell reactivity may spread to other epitopes within the allogeneic MHC molecule, as well as to other alloantigens expressed by graft tissue. Both quantitative and qualitative alterations in T cell allopeptide reactivity are associated with increased risk of cellular and/or humoral rejection. These studies provide a basis for the design of new therapeutic strategies and for immunologic monitoring of transplant recipients.     

Human T‐lymphotropic virus type 1 infection and solid organ transplantation

HTLV infection appears to be more common among renal transplant candidates than in the related general population. HTLV‐1‐associated diseases may occur in carriers who are transplanted but there is insufficient evidence to confirm whether these occur more frequently as a result of the associated immunosuppression. Consequently, pre‐existing HTLV‐1 infection should not be considered a contra‐indication to transplantation. The risk of transmission of HTLV‐1 through solid organ transplantation from a confirmed infected donor is unknown. There are anecdotes of multiple infections from a single donor. Biologically due to the significant volume of blood and the lack of storage, transmission would be expected to be higher than following blood transfusion. The rate of subsequent disease is unknown, but there are now 11 reports of HAM and 2 of ATL occurring within 4 years of transplantation associated infection. There are insufficient data to know whether the time from infection to onset of disease and the rate of progression differ from transmission through other routes, but early onset and rapid progression is a concern. Responses to enhanced immunosuppression for the treatment of HAM are variable. The risk of HTLV‐1 associated disease in exchange for a life‐saving major organ transplantation from an infected donor might be considered worth taking by some HTLV‐1 uninfected patients. Peri‐transplantation antiretroviral prophylaxis with zidovudine and raltegravir is biologically sound but therapeutically unproven. The risks related to HTLV‐1 infection appear to preclude the use of any other tissue. All transplant donors should be screened for HTLV‐1 infection regardless of perceived risk.     

Prophylaxis for CMV should not now replace pre-emptive therapy in solid organ transplantation

Pre-emptive therapy (PET) initiated on the basis of HCMV positivity in the blood using sensitive methods such as PCR, nucleic acid sequence based amplification or antigenaemia offers several advantages for the management of HCMV infection. These include the ability to target antiviral drug therapy to those most at risk of future disease, minimising drug exposure and maximising cost-benefit. In addition, allowing limited replication to occur also provides immune stimulation which will be important for future control of HCMV replication. In contrast, prophylaxis is a high-cost strategy which exposes all patients to potentially toxic drugs, does not facilitate immune priming and leads to the development of late HCMV infection and disease in high-risk patients.     

器官移植中的基因治疗

基因治疗是解决器官移植排斥一个很有潜力的方案，而且有着独特的优点。器官移植是把一个个体的组织或器官切取下来移植给另一个个体，这就为我们提供了一个在体外使用转基因载体改造供体器官或组织的时机。这样就可以在局部表达免疫移植抑制分子，让受者免于全身使用免疫抑制剂，而且有望达到抗原特异性耐受的状态。现就有关内容综述如下。     

肾移植后巨细胞病毒感染的检测

背景：肾移植后因患者细胞免疫、体液免疫均明显下降,易发生各种类型感染,其中以巨细胞病毒感染多见,且有较高的发病率和病死率,早期准确的检测有利于指导临床治疗。 目的：对肾移植后巨细胞病毒感染检测研究的文献资料进行多层次的探讨分析。 方法：以电子检索的方式对CNKI数据库2002-01/2011-12 有关肾移植后巨细胞病毒感染检测研究的文献进行分析,采用检索词为“肾移植(renal transplantation);巨细胞病毒(cytomegalovirus);BK病毒(BK virus);疱疹病毒(herpes virus)”。巨细胞病毒是肾移植后感染的主要病原体,与肾移植后肺炎、肝炎、视网膜炎及肾移植后急、慢性排斥反应的发生有着密切的联系。 结果与结论：肾移植后巨细胞病毒感染的检测方法不断改进,检测方法较多,目前尚无一种理想的方法可以早期及时准确检测出活动性巨细胞病毒感染,主要是将血清学检测、荧光免疫标记检测、抗原抗体检测以及基因检测进行相结合来检测诊断肾移植后巨细胞病毒感染,尤其是巨细胞病毒晚期抗原(pp65)检测迅速发展,提高了巨细胞病毒感染检测的特异性及敏感性,为临床诊断及预防治疗提供了重要的参考依据。     

The risk of cytomegalovirus infection in non-myeloablative peripheral stem cell transplantation compared with conventional bone marrow transplantation

Non-myeloablative allogeneic peripheral stem cell transplantation (NST) is a novel therapeutic strategy for patients with hematologic malignancies. Whether non-myeloablative transplants are associated with increased risk of cytomegalovirus (CMV) infections is unknown. To clarify this issue, we compared the outcome of CMV infection following 24 allogeneic non-myeloablative peripheral blood stem cell transplants and 40 conventional bone marrow transplants (CBT). The NST regimen consisted (mg/kg). Twelve patients (50%) in the NST group and 17 (43%) in the CBT group developed positive antigenemia before day 100 (p=0.60). The time to the first appearance of positive antigenemia was not different between these two groups (p=0.40), and two groups showed similar initial and maximal antigenemia values (p=0.56 and p=0.68, respectively). Only one case of CMV colitis developed in the CBT group whereas CMV disease did not develop in the NST group. Although statistically insignificant, the treatment response against CMV antigenemia using ganciclovir was in favor of NST group. In conclusion, there was no difference in the risk of CMV infection between NST group and CBT group. Further prospective and controlled study is needed to clarify the impact of non-myeloablative procedure on the outcome of CMV infection.     

Systematic review of ganciclovir pharmacodynamics during the prevention of cytomegalovirus infection in adult solid organ transplant recipients

Human cytomegalovirus (CMV) represents the most common infection among recipients of solid organ transplants (SOTs). Previous meta‐analysis showed 0.8% of SOT recipients developed CMV disease whilst receiving valganciclovir (ValGCV) prophylaxis. However, the clinical utility of monitoring ganciclovir (GCV) blood concentrations is unclear. We systematically reviewed the association between GCV concentrations during prophylaxis and the incidence of CMV. MEDLINE and EMBASE databases were searched for studies between 1946 and 2018, where GCV pharmacokinetics and incidence of CMV viraemia or disease in SOT were available. Research designs included randomised trials, comparative, prospective cohort, retrospective, or case report studies. Only human adult studies were included, with English language restriction. The 11 studies that met the eligibility criteria included 610 participants receiving GCV or ValGCV prophylaxis. Quality assessment showed 2/4 randomised trials, 4/6 cohort studies, and 1/1 case report were of high quality. Despite dose adjustments for renal impairment, mean GCV exposures for patients were heterogeneous and ranged between 28 and 53.7 μg·h/mL across three randomised trials. The incidence of CMV infection and disease ranged from 0% to 50% and 0% to 3.1%, respectively, with follow up between 3 to 9 months. One study showed statistical power in determining relationship, where GCV exposure at 40 to 50 μg·h/mL in high‐risk SOT recipients was associated with a reduced risk of viraemia. Clinical monitoring for GCV exposure can be applied to high‐risk SOT recipients during ValGCV prophylaxis; however, further studies are needed to determine the utility of monitoring in all SOT recipients.     

源自供者实体器官移植的受者感染

背景：目前,器官移植受者所面临的最大危险来自移植后感染。随着实体器官移植的广泛开展,器官来源严重短缺,大量边缘供者器官被采用,通过移植过程将供者的感染性疾病传播给受者的病例时有报道,其中包括一些罕见疾病的传播。2009年美国传染性疾病咨询委员会提出包括肿瘤在内的源自供者的传染性疾病的等级评判标准,为源自供者的受者感染性疾病的诊断提供了统一的标准。 目的：综述国内外关于源自供者的实体器官移植受者感染性事件的研究概况。 方法：应用计算机检索PubMed数据库、中国生物医学文献数据库、CNKI数据库及万方数据库2000-01/2010-01有关源自供者的实体器官移植受者感染性事件的文章,英文检索词为“transmission, organ transplantation”。中文检索词为“器官移植,供者,传染”。同时根据所获得的文献进行引文检索并对部分疾病进行补充检索。排除组织移植、不切题、重复或陈旧性文献。 结果与结论：共保留48篇文献进一步分析。近10年来,源自供者的实体器官移植受者感染性事件的报道涉及细菌、病毒以及寄生虫传染,但绝大部分为罕见疾病的报道。源自供者的受者感染性事件的发生,无疑对目前广泛适用的供者筛查标准提出了挑战,但其毕竟只是小概率事件,并不影响器官移植的开展。     

Invasive mycosis in solid organ transplantation]

Invasive mycosis in solid organ transplantation is mainly caused by Candida and Aspergillus, and its risk is higher in small bowel, liver, pancreas, and lung transplantation. Although limited analyses propose not a few risk factors for invasive mycosis in respective transplanted organs, the efficacy of prophylactic use of antifungal agents or preemptive treatments based on the information is not fully supported by prospective randomized controlled clinical data. The final guideline should be helpful for tailor-made evidence-based management based on the stratification of patients by pretransplant, surgical, immunosuppressive and organ specific characteristics. The process of repeated proposals and verification in a large number of patients is necessary.     

The anatomic pathologist and solid organ transplantation

Pathologists continue to play important roles in the management of solid organ allografts. These organs experience the same diseases in the corresponding non-transplant organs, but the added context of immunosuppression and alloimmunity introduces several unique factors that the pathologist has to take into context while evaluating biopsies from this group of patients. This introduction to the current miniseries highlights these special considerations and discusses the factors that differentiate transplant biopsy from other scenarios, with a view to emphasizing their importance as they enhance the pathologist's ability to obtain and provide optimum information from allograft biopsies.     

Graft microvascular disease in solid organ transplantation

Alloimmune inflammation damages the microvasculature of solid organ transplants during acute rejection. Although immunosuppressive drugs diminish the inflammatory response, they do not directly promote vascular repair. Repetitive microvascular injury with insufficient regeneration results in prolonged tissue hypoxia and fibrotic remodeling. While clinical studies show that a loss of the microvascular circulation precedes and may act as an initiating factor for the development of chronic rejection, preclinical studies demonstrate that improved microvascular perfusion during acute rejection delays and attenuates tissue fibrosis. Therefore, preservation of a functional microvasculature may represent an effective therapeutic strategy for preventing chronic rejection. Here, we review recent advances in our understanding of the role of the microvasculature in the long-term survival of transplanted solid organs. We also highlight microvessel-centered therapeutic strategies for prolonging the survival of solid organ transplants.     

Fungal infections in solid organ transplantation.

Fungal infections in solid organ transplant recipients continue to be a significant cause of morbidity and mortality. Candida spp. and Aspergillus spp. account for most invasive fungal infections. The incidence of fungal infection varies with type of solid organ transplant. Liver transplant recipients have highest reported incidence of candida infections while lung transplant recipients have highest rate of Aspergillus infections. Recent epidemiological studies suggest the emergence of resistant strains of candida as well as mycelial fungi other than Aspergillus in these patients. The current review incorporates the recent changes in the epidemiology of fungal infections in solid organ transplant recipients and highlights the newer data on the diagnosis, prophylaxis and treatment of fungal infections in these patients.