Infectious disease risks in xenotransplantation

Hurdles exist to clinical xenotransplantation including potential infectious transmission from nonhuman species to xenograft recipients. In anticipation of clinical trials of xenotransplantation, the associated infectious risks have been investigated. Swine and immunocompromised humans share some potential pathogens. Swine herpesviruses including porcine cytomegalovirus (PCMV) and porcine lymphotropic herpesvirus (PLHV) are largely species‐specific and do not, generally, infect human cells. Human cellular receptors exist for porcine endogenous retrovirus (PERV), which infects certain human‐derived cell lines in vitro. PERV‐inactivated pigs have been produced recently. Human infection due to PERV has not been described. A screening paradigm can be applied to exclude potential human pathogens from “designated pathogen free” breeding colonies. Various microbiological assays have been developed for screening and diagnosis including antibody‐based tests and qualitative and quantitative molecular assays for viruses. Additional assays may be required to diagnose pig‐specific organisms in human xenograft recipients. Significant progress has been made in the evaluation of the potential infectious risks of clinical xenotransplantation. Infectious risk would be amplified by intensive immunosuppression. The available data suggest that risks of xenotransplant‐associated recipient infection are manageable and that clinical trials can be performed safely. Possible infectious risks of xenotransplantation to the community at large are undefined but merit consideration.     

Infectious complications after kidney transplantation: current epidemiology and associated risk factors

BACKGROUND: The impact of newer immunosuppressive and antimicrobial prophylactic agents on the pattern of infectious complications following kidney transplantation has not been well studied. METHODS: This is an observational study in 127 adult recipients transplanted from 2001 to 2004. Patients received thymoglobulin (ATG) (50%) or basiliximab (50%) for induction and were maintained on mycophenolate mofetil, either tacrolimus (73%) or sirolimus (SRL) (27%), and prednisone (79%). Antimicrobial prophylaxis included perioperative cefazolin, trimethoprim/sulfamethaxazole for six months, valganciclovir for three months and nystatin for two months. Regression models were used to examine the association of various factors with infections. RESULTS: We observed 127 infections in 65 patients, consisting of urinary tract infection (UTI) (47%), viral infections (17%), pneumonia (8%) and surgical wound infections (7%). UTI was the most common infection in all post-transplant periods. Enterococcus spp. (33%) and Escherichia coli (21%) were the most prevalent uropathogens. Of six patients with cytomegalovirus infection, none had tissue-invasive disease. There were no cases of pneumocystis pneumonia or BK nephropathy. Six patients developed fungal infections. Two deaths due to disseminated Rhizopus and Candida albicans accounted for a 1.5% infection-related mortality. Retransplantation and ureteral stents were independently associated with UTI (OR=4.5 and 2.9, p=0.06 and 0.03, respectively), as were ATG and SRL with bacterial infections (OR=3.3 and 2.5, p=0.009 and 0.047, respectively). CONCLUSION: This study suggests that the use of newer immunosuppressive agents in recent years is associated with some changes in the epidemiology of post-transplant infections. Enterococci have become the predominant uropathogen. Invasive fungal infections, although rare, are often fatal.     

Infectious risk and locoregional anaesthesia

We analysed the data on the risk of infection during practice of locoregional anaesthesia (LRA) and propose recommendations for its prevention. The epidemiologic data show that the incidence is very low. The risk of LBA during sepsis is uncertain and the data are often contradictory. The benefit-risk ratio must be considered, specifically in obstetrics. Precautions which must be followed during the practice of LRA are discussed.     

Donor‐derived infections and infectious risk in xenotransplantation and allotransplantation

Post‐transplantation infections are common in allograft recipients and should be expected in all immunocompromised hosts. Based on the need for immunosuppression in xenotransplantation, procedures developed to enhance safety in allotransplantation can be applied in future xenotransplantation clinical trials. Standardized approaches can be developed to guide the evaluation of common infectious syndromes in xenograft recipients. The opportunity created by screening of swine intended as xenograft donors has equal applicability to allotransplantation—notably broader screening strategies for allograft donors such as use of advanced sequencing modalities including broad‐range molecular probes, microarrays, and high‐throughput pyrosequencing. Considerations in management of allotransplant‐ and xenotransplant‐associated infections are largely the same. Experience in xenotransplantation will continue to inform thinking regarding donor‐derived infections in allotransplantation. We expect that experience in managing complex allotransplant recipients will similarly inform clinical trials in xenotransplantation.     

移植相关人群对异种肾移植的态度及影响因素

目的 调查移植相关人群对于异种肾移植的态度及影响因素。 方法 2022年6月至2023年1月,对等待肾移植患者、肾移植术后患者、患者家属及医学生进行分层随机抽样,每个群体抽取400名,共1 600名进行自制问卷调查。分析受访者的一般资料、对异种肾移植的态度及不能接受异种肾移植的原因。分析受访者对异种肾移植态度的影响因素。 结果 共回收有效问卷1 493份,回收有效率93.31%。能接受同种异体肾移植手术的占93.10%;知晓异种肾移植的占66.78%。795名受访者表示“在异种肾移植与同种异体肾移植有着相同结果及风险时”能接受异种肾移植;698名表示“不能”或“不确定”能否接受异种肾移植（χ²=16.409,P=0.001）。698名表示“不能”或“不确定”能否接受异种肾移植的受访者中,在不符合同种异体肾移植的条件下,愿意接受异种肾移植的占10.9%;如果与同种异体肾移植相比,异种肾移植有着更小的风险及更好的预后的条件下,愿意接受异种肾移植的占35.8%;如果与同种异体肾移植相比,异种肾移植等待时间更短,愿意接受异种移植的占21.2%;如果与同种异体肾移植相比,异种肾移植花费更少,愿意接受异种肾移植的占24.5%。受访者不能接受异种肾移植的主要原因为担心手术风险及担心其他未知风险。多因素分析结果显示,长期居住在城镇的受访者、能接受同种异体肾移植的受访者、知晓异种肾移植的受访者对异种肾移植态度更积极。 结论  不同移植相关人群对异种肾移植态度存在差别,总体态度良好。积极推进异种肾移植的研究、开展相关科普教育有利于提高公众对异种肾移植的接受度。     

Infectious risk from ventriculostomy]

Ventriculostomy is a useful technique for the management of acute hydrocephalus or increased intracranial pressure. The mean rate of ventricular infections is 10%. This risk can be decreased by selecting indications, adherence to aseptic insertion techniques, avoiding CSF leakage, tunneling the catheter, using closed systems and limiting line manipulations. Duration of ventriculostomy drainage remains controversial, as well as systematic change of drain every five days of drainage. The value of local or general prophylactic antibiotic treatment remains to be substantiated.     

Infection in xenotransplantation

Advances in transplantation immunology have enhanced the possibility of xenotransplantation as a therapeutic option for end-stage organ failure. The potential spread of animal-derived pathogens to the recipient and to the general population, termed "xenosis," is a potential complication of interspecies transplantation. Recognition of such novel infections may be complicated by infections due to altered microbiologic behavior and clinical symptomatology of these organisms, particularly in the immunocompromised xenograft recipient. Particular concern exists over the activation of latent viruses, including retroviruses, from xenograft tissues. Based on experience with human allogeneic transplantation, those pathogens considered most likely to cause human disease can be excluded prospectively from herds of animals developed for organ donation. Research is needed into the activation and behavior of retroviruses and other potential pathogens in xenotransplantation. Xenotransplantation may also provide unique opportunities not only for the care of patients with organ failure, but in the therapy of individuals with chronic infections to which the xenograft may be resistant. Clinical protocols must be developed so as to enhance the safety of the recipient and of the community-at-large.     

Coagulation in xenotransplantation

Following either discordant transplantation of porcine organs into primate recipients or after ex vivo perfusion of porcine organs with human blood, a profound activation of the primate/human blood coagulation can be observed. This activation may result in thrombotic microangiopathy and changes of coagulation resembling disseminated intravascular coagulation with subsequent death of the recipient animals. There are several factors contributing to this pathology including endothelial cell activation, activation of human blood cells, thrombocyte activation and incompatibilities of molecules regarding to control coagulation. Several potentially important molecular incompatibilities between the porcine and the primate coagulation system have been noted: The inability of porcine tissue factor pathway inhibitor (TFPI) to adequately neutralize human factor Xa (FXa), the aberrant activation of both human prothrombin and FX by porcine endothelial cells and the failure of the porcine natural anticoagulant thrombomodulin to activate the anti‐coagulant human protein C. Normal hemostasis is a complex balance between pro‐ and antithrombotic pathways. These pathways are balanced by inhibitory systems including the heparin‐antithrombin interaction, TFPI, the generation of activated protein C by a proper thrombomodulin/thrombin interaction and the fibrinolytic system. To achieve normal haemostasis after xenotransplantation it is important to overcome the known molecular incompatibilities (i.e. by transgenic organs) and to reliably prevent the derangement of coagulation.     

Coagulation in xenotransplantation

After xenogenic kidney transplantation or perfusion activation of porcine endothelial cells and of the recipients coagulation system can be observed. There are several factors contributing to this pathology including reperfusion injury, binding of xenoreactive natural antibodies, complement activation, secretion of TNF, activation of human blood cells, thrombocyte activation and incompatibilities of molecules regarding to control coagulation. To investigate the following processes after the contact of the human blood with the porcine endothelium we developed an ex vivo perfusion model where porcine kidneys were perfused with either porcine (autologous) or human (xenogenic) blood. During perfusion blood samples were collected and the coagulation parameters D Dimer, Thrombin‐antithrombin complexes (TAT), fibrinogen and antithrombin were measured. At the end of perfusion tissue samples were obtained for histological analyses and QPCR. The xenogenic perfusion experiments revealed a profound activation of the human blood coagulation shown by increase of D Dimer and TAT and decrease of fibrinogen and antithrombin. In addition, on histology could be multiple microthrombi observed. During the autologous perfusion, no signs of activation of the blood coagulation could be observed. The D dimer and TAT remained low and there was no consumption of fibrinogen and antithrombin. Assessment of endothelial cell activation showed a drastic increase of the activation markers VCAM‐1 and E‐Selectin only after xenogenic perfusion. Addition of the natural anticoagulant activated protein C abolished the derangement of coagulation and was able to reduce endothelial cell activation. To achieve normal haemostasis and endothelial cell function after xenotransplantation it is important to overcome the known molecular incompatibilities, to reliably prevent the derangement of coagulation and endothelial cell activation.     

Immunodepletion in xenotransplantation

Xenograft transplantation is perhaps the most immunologically difficult problem in transplantation today. An overwhelming hyperacute rejection reaction (HAR) occurs within minutes of organ implantation. Preformed antibodies are thought to initiate this process. We used a pig-to-dog renal xenograft transplant model and investigated methods of decreasing the severity of hyperacute rejection. Female pigs weighing 15-20 kg were used as donors. Recipients were mongrel dogs weighing 15-25 kg. Experimental dogs were all given a number of treatments of IgG depletion using an antibody removal system (Dupont-Excorim). This machine immunoadsorbs plasma against a column containing immobilized staphylococcal protein A, which is known to bind the IgG Fc receptor. An 84% reduction in the IgG levels and a 71% reduction in IgM levels was achieved. Postoperative assessment was made of urine output, time to onset of HAR, and histopathological examination of the rejected kidneys. Although cross-matches between donor lymphocytes and recipient sera remained strongly positive in the treated dogs, there was a two- to fourfold reduction in the titers. The time to onset of HAR was prolonged in the experimental group, and the urine output was increased slightly. The histopathologic changes in the experimental group generally showed signs of HAR, but of less intensity than in the nonimmunodepleted control group.     

Heart-lung xenotransplantation in primates

Heart and heart-lung xenografts are a potential solution to the shortage of donors. Concern over the adequacy of conventional immunosuppression in prevention of xenograft rejection, however, has hindered their use. Cyclosporine has not been successful in suppressing the rejection process in cardiac xenotransplantation, and other methods of immunosuppression need to be investigated. Therefore we studied the effect of preoperative total lymphoid irradiation (TLI) in combination with cyclosporine in a primate heart-lung xenograft model using cynomolgus monkey donors and baboon recipients. Heart-lung grafts were harvested from donors and transplanted orthotopically in baboons with use of cardiopulmonary bypass. Recipients were treated in one of three groups: (1) cyclosporine and steroids (controls), (2) cyclosporine and steroids plus TLI 20 Gy, or (3) cyclosporine, steroids, antithymocyte globulin, and TLI 6 Gy. Mean survival time of the baboons treated with cyclosporine and steroids was 8 +/- 0.6 days. The group receiving 20 Gy TLI had prohibitive perioperative mortality; however, one baboon lived an additional 90 days, and at autopsy the heart showed minimal rejection. Treatment with TLI at 6 Gy in combination with cyclosporine, antithymocyte globulin, and steroids comparatively prolonged survival (16 +/- 7.8 vs 8 +/- 0.6 days; p less than 0.001), and all animals in this group died of infection, with only minimal evidence of heart rejection noted in animals surviving 30 days. We conclude that the addition of TLI and antithymocyte globulin to cyclosporine-based standard immunosuppression is a potent immunosuppressant in heart-lung xenotransplantation; nevertheless, infection remains a common complication.