肝移植术后严重感染状态下的严重排斥反应3例报告

回顾性分析收治的3例肝移植患者在严重感染状态下免疫抑制治疗的临床资料。结果示1例活体辅助肝移植患者几乎完全停用免疫抑制剂后发生严重排斥反应导致移植肝丧失；1例老年肝移植患者免疫抑制剂减量后出现严重排斥反应，立即予激素冲击治疗获良好效果；1例患者大幅减少免疫抑制剂后发生严重排斥反应，导致门静脉血栓形成而被迫再次肝移植。提示肝移植术后严重感染状态下行免疫抑制剂减量或停用时须密切观察是否发生急性排斥反应；一旦发生，宜果断予加强免疫抑制剂治疗。     

暂停免疫抑制剂对肝移植术后严重感染疗效的探讨

目的 探讨肝移植术后并发严重感染暂时停用免疫抑制剂的安全性及有效性。方法 回顾性分析2003年10月至2006年11月期间因肝移植术后并发严重感染而14次停用免疫抑制剂的12名患者。结果 所有患者停用免疫抑制剂时间平均为14.57d（5～28d）。共6名患者死亡，死亡率为50.0%。排斥反应发生率为8.3%，经恢复使用原剂量的他克莫司后逆转。2005年9月前6名患者共8次停用免疫抑制剂（每次停用时间〈20d，为A组），死亡5例，死亡率为83.3%。2005年10月后6名患者采用较长时间停用免疫抑制剂（≥20d，为B组），死亡1例，死亡率为16.7%，明显低于A组（Х^2=0.08，P=0.04）。结论 暂时停用免疫抑制剂有助于控制肝移植术后严重感染，发生急性排斥反应后绝大部分患者均可以通过恢复使用免疫抑制剂逆转。     

肝移植急性排斥反应预防与治疗速查手册(续)

四、肝移植围手术期常规免疫抑制方案 以钙调磷酸酶抑制剂（CNI）为基础的三联免疫抑制方案，由环孢素A（或他克莫司）、霉酚酸酯及皮质激素组成，或在上述三联免疫抑制方案基础上加以抗白细胞介素2受体（IL-2R）单克隆抗体进行诱导的四联免疫抑制方案。各种免疫抑制剂的应用方法如下：     

原位肝移植术后真菌感染的诊治

目的 探讨原位肝移植术后真菌感染的诊断和治疗。方法 58例肝移植患者术后怀疑真菌感染时，行体液（痰、血、尿、胆汁、引流液等）或导管真菌培养，结合胸腹部CT影像学检查、活组织检查及诊断性治疗结果综合判断，一旦诊断确定，即给予氟康唑治疗，无效者改用伊曲康唑和两性霉素B，同时调整免疫抑制治疗方案。结果 58例患者中，16例术后并发真菌感染21例次（5例患者发生两次以上、不同部位或不同菌株的感染），感染发生率为27．6％（16／58），感染发生在术后4～38d，感染好发部位依次为肺（28．6％）、肠道（19．0％）、泌尿系统（14．3％）、腹腔（14．3％）、切口（9．5％）、血液（4．8％）、胆管（4．8％）及肝脏（4．8％）。在21例次真菌感染中，念珠菌感染占85．7％，曲霉菌感染占14．3％。氟康唑治疗有效者占66．7％，伊曲康唑治疗有效者占14．3％，两性霉素B治疗有效者占14．3％，1例（4．7％）各种抗真菌药物治疗均无效，治疗总有效率为95．2％。结论 肝移植术后真菌感染的发生率较高，依据影像学检查、病原学检查及活组织检查综合判断真菌感染，及时选用氟康唑、伊曲康唑及两性霉素B治疗。     

肝移植术后肺部真菌感染的诊断和治疗

目的探讨肝移植术后肺部真菌感染的早期诊断及治疗方法。方法回顾分析20例肝移植术后肺部真菌感染患者的临床资料,分析其原发病、免疫状态、感染真菌的种类及抗真菌药物的应用。结果20例患者念珠菌感染17例,死亡2例,曲霉菌感染3例,死亡2例。氟康唑、伊曲康唑、两性霉素B治疗有效率70％,伏立康唑、卡泊芬净治疗有效率100％。结论肝移植术后真菌感染高发,以危重患者为主要目标人群,发生早,病情重。诊断分三级,达到临床诊断即应及早治疗。治疗以伏立康唑为首选,严重感染者联合应用卡泊芬净效果良好。     

肝移植后并发严重感染时暂停使用免疫抑制剂11例

目的 探讨肝移植后并发严重感染时暂停使用免疫抑制剂的安全性及有效性.方法 11例肝移植患者,术后7例采用他克莫司(FK506)及甲泼尼龙(MP)预防排斥反应,4例采用FK506、霉酚酸酯(MMF)及MP预防排斥反应,因感染共13次暂停使用免疫抑制剂.感染发生于术后2～262 d,确诊后,根据药物敏感试验结果 使用敏感的抗细菌和(或)抗真菌药.停用MP及MMF,并降低FK506的用量,当感染无明显改善或继续发展时,完全停用免疫抑制剂.结果 13次停用免疫抑制剂的时间为5～26 d,平均为13.5 d.2005年5月之前的6例患者共8次停用免疫抑制剂.每次停用时间均少于10 d,6例中.仅1例痊愈出院,其余5例的感染未得到有效控制,死于多器官功能衰竭.2005年5月之后的5例.每次停用免疫抑制剂的时间超过20 d,5例中,2例分别由于肺动脉栓塞和肝动脉血栓形成合并严重感染,未能治愈外,其余3例痊愈出院,其中1例在停用免疫抑制剂后25 d,血丙氨酸转氨酶及天冬氨酸转氨酶异常升高4倍以上,经肝脏穿刺活检证实为轻度急性排斥反应,在恢复使用原剂量的FK506后,肝功能逐渐恢复正常.结论肝移植后并发严重感染时可暂停使用免疫抑制剂,期间即使发生急性排斥反应,也较容易逆转.     

肝移植术后迟发型急性排斥反应的发生和治疗

目的探讨肝移植术后迟发型急性排斥反应（lateacuterejection，LAR）的发生率、处理和预后。方法回顾性分析我科2004年8月至2006年8月收治的15例迟发型急性排斥反应（肝移植术6个月后发生的急性排斥反应）患者的临床资料。结果15例LAR发生在术后6．6—27个月，平均（14．7±7．5）个月。其中男14例，女1例。年龄32～66岁，平均年龄（49．5±12．7）岁。原发疾病为重症肝炎或肝功能衰竭者8例，占53．3％（8／15）；发生于血型不合移植者2例，免疫抑制治疗方案为单一普乐可复（FK506）治疗8例，单一环孢素A（CsA）治疗3例，已经停用激素13例，占86．7％。属于免疫抑制剂量不足者共10例，占66．7％。免疫抑制剂浓度正常范围者5例。按Banff分级标准排斥反应的程度为轻度者9例，中度6例，无重度排斥反应发生。治疗方法均首先加强或调整免疫抑制治疗，包括提高药物浓度、FK506／CsA转换、联合其他免疫抑制剂和激素冲击治疗，3例患者需长期口服激素。总的治愈率为80％，3例患者逐渐出现缺血型胆道病变，其中1例行再移植后死亡。结论迟发型急性排斥反应是肝移植术后常见但预后较好的并发症之一，免疫抑制不足是其发生的主要原因，及时地加强免疫抑制治疗可逆转排斥反应。     

肾移植术后全身播散性曲霉菌病三例

目的 探讨肾移植术后全身播散性曲霉菌病的诊断和治疗.方法 回顾性分析1999至2006年间发生的3例肾移植术后并发全身播散性曲霉菌病受者的临床资料.结果 3例受者均不同程度地具有高龄、长期糖尿病病史、伴有其他感染或长期使用强效广谱抗生素等易造成曲霉菌重症感染的高危因素.受者发病前均处于过度免疫抑制状态.经过积极抗真菌治疗,2例治愈,1例发生多器官功能衰竭.结论 应高度警惕过度免疫抑制的高危受者的全身播散性真菌感染;及时诊断,尽快抗真菌治疗,并适当减少或停用免疫抑制剂是非常关键的措施.     

狼疮性肾炎不同免疫抑制治疗方案合并感染的相关分析

目的：分析目前临床上常用的不同免疫抑制治疗方案使用与狼疮性肾炎（LN）患者合并感染的相关性。方法：回顾性分析我院肾内科2000年3月～2010年4月532例LN患者的临床以及实验室资料,男55例,女477例,其中41例合并各种病原微生物感染。对41例感染患者的一般资料、病理类型、SLE疾病活动指数（SLEDAI）、免疫抑制剂的种类、感染部位、感染微生物用SPSS13.0软件进行统计分析。结果：532例患者中41例（7.71%）发生感染,涉及免疫抑制剂分别为激素,环磷酰胺（CTX）,霉酚酸酯（MMF）,普乐可复（FK506）,硫唑嘌呤（AZA）。感染的微生物依次为细菌、真菌、病毒,累及呼吸系统、泌尿系统、皮肤等等。激素＋CTX方案易发生细菌或真菌感染（P〈0.05）,激素＋MMF方案易发生病毒感染（P〈0.05）,激素＋CTX＋MMF方案易发生真菌感染（P〈0.05）。感染微生物的种类与感染部位显著相关（P〈0.05）,细菌感染多发生于泌尿系统,病毒、真菌感染最常累及呼吸系统。MMF的使用时间与感染的微生物、部位分别进行相关性研究未发现相关性（P〉0.05）。结论：LN患者并发感染的致病菌主要为细菌感染,最常见的感染部位为呼吸系统。此次的研究表明激素＋CTX方案易发生细菌或真菌感染,激素＋MMF方案易发生病毒感染,激素＋CTX＋MMF方案易发生真菌感染。     

肝移植术后免疫抑制剂的替换应用

目的 探讨和总结肝脏移植术后免疫抑制剂的替换应用情况和经验。方法 回顾性分析我院1993年4月－2001年7月施行的67例肝脏移植，对48例早期肝移植患者中发生的免疫抑制剂替换应用情况进行总结。结果 48例患者中，21例（43．8％）因术后出现排斥反应或严重毒副作用而替换为其它免疫抑制方案。环孢素A（CsA 硫唑嘌呤（Aza)＋激素方案组（31例）中，15例（48．4％）进行替换；CsA 霉酚酸酯（MMF）＋激素组（14例）中，6例（43％）进行替换。发生排斥反应者常规应用激素冲击治疗，同时替换免疫抑制剂，将CsA替换为他克莫司（FK506）或提高CsA剂量，可获得有效控制；出现药物性肝损害者应及时减少CsA用量或成FK506，其肝功能多能改善；出现肾功能损害者应减少CsA用量并改联用MMF，或替换成FK506后可有效挽救肾功能；白细胞减少或严重感染者，应停用Aza或MMF，或将CsA改为FK506后可有效挽救肾功能；白细胞减少或严重感染者，应停用Aza或MMF，或将CsA改为FK506；神经系统病变经更换免疫抑制剂可以好转。结论 合理应用免疫抑制剂是提高肝移植成功率的关键之一；治疗中应视具体情况及时、果断、合理地转换免疫抑制剂，可以有效控制排斥反应、毒副作用及相关并发症，提高移植肝的存活率。     

Primary immunosuppression regimen of rapid steroid withdrawal after living related liver transplantation: a single-center experience

AIM: Corticosteroids have been considered the mainstay of immunosuppressive therapy after liver transplantation. However, the side effects of long-term steroid use such as diabetes, infections, and bone disease, including growth retardation in children, are serious problems. Our immunosuppression regimen includes FK506 and steroid withdrawal by 30 days after transplantation. The aim of this study was to determine the outcomes of liver transplant, using this immunosuppressive regimen. PATIENTS: Fifteen primary liver transplant recipients were performed between January 1994 and May 2003 and data were reviewed retrospectively. Eight pediatric and four adult recipients, who had survived more than 3 months after transplantation, were included in this sample. The immunosuppressive regimen consisted of FK 506 (Prograf), initially at doses of 0.03 mg/kg, with dose adjustments to achieve daily trough levels of approximately 10 to 12 ng/mL, and predonisone, initially at 4 mg/kg/d, with a taper and cessation by 30 days when the graft was stable. RESULTS: All recipients were successfully withdrawn by 30 days. Acute rejection episodes occurred in three patients, no patient was diagnosed with chronic rejection. The acute rejection-free rate at 5 year was 74.1%. No recipient had diabetes, serious infections or bone disease. CONCLUSION: Our primary immunosuppressive regimen of rapid steroid withdrawal is safe with regard to acute and chronic rejection with benefits upon steroid-related side effects.     

Fungal Infection in Heart Transplant Recipients With Severe Sepsis: Single-Center Experience

The objective of this study was to describe in heart transplant recipients severe sepsis due to fungal infection, which is associated with high mortality. This was a retrospective study including 366 patients who underwent heart transplantation from 1987 to 2009 in whom severe sepsis due to fungal infection developed, with multiple-organ failure. Sepsis was diagnosed on the basis of a positive culture for the infective agent, such as Cryptococcus, Aspergillus, Candida, or Nocardia, from an appropriate source such as blood, wound, or sputum. In 10 patients, severe sepsis due to fungal infection was treated temporally by reducing or sparing immunosuppression; 7 of these patients survived after intensive care. Only 1 patient required pulsed therapy because of an acute rejection episode. Early diagnosis with aggressive diagnostic techniques and use of combination therapy must be considered to reduce the risk of death in heart transplant recipients with fungal infection.     

肝移植临床可操作性耐受的研究现状及展望

长期免疫抑制治疗可增加肝移植受者感染性疾病和癌症的发生率和病死率,且现今免疫抑制治疗无法完全阻止和延缓慢性移植物排斥反应的发生。临床可操作性耐受（COT）是指不接受免疫抑制治疗而移植物长期存活,无有害的免疫应答证据且对肿瘤和感染有正常的免疫反应,被认为是避免移植物排斥反应发生的终极方案。20％～30％的肝移植受者在撤除免疫抑制剂后可产生自发性耐受,某些细胞和分子标志物被证实与肝移植受者免疫耐受状态有关。目前有研究表明嵌合体、诱导免疫调节细胞等方法可以诱导形成免疫耐受,但总体来说,肝移植COT的相关研究还处于起步阶段。本文就肝移植COT的临床证据、免疫监视、生物标志物和可能诱导耐受的策略等作一综述,以期为后续研究提供思路。     

肝移植治疗终末期自身免疫性肝病的预后分析

目的  探讨肝移植治疗终末期自身免疫性肝病(AILD)的预后情况。方法  回顾性分析1996年5月至2013年4月在第二军医大学附属长征医院实施原位肝移植术的48例终末期AILD受者的临床资料。计算受者的术后累积生存率,分析死亡病例的死因,了解术后排斥反应、病毒性肝炎新发感染及AILD复发情况。结果  48例AILD受者中,存活38例,AILD受者术后5年累积生存率为76%。10例死亡受者的死亡原因包括多器官功能衰竭、移植肝衰竭、脓毒症、肺部感染、出血、肝动脉栓塞、肾衰竭。48例AILD受者中,肝移植术后发生急性排斥反应者9例(19%),有3例分别在术后1~2年内新发乙型肝炎病毒感染,有2例原发性胆汁性肝硬化受者于术后2年出现原发病复发,经积极治疗均长期生存。结论  终末期AILD肝移植受者多数可获得长期生存,应重视肝移植术后早期免疫抑制方案的制定,预防感染及排斥反应和术后新发病毒性肝炎,及时发现原发病复发等问题。     

Airway anastomosis complications in de novo lung transplantation with sirolimus-based immunosuppression.

A prospective, pilot trial was started to evaluate the effect of a sirolimus-based immunosuppressive regimen on acute and chronic rejection in de novo lung transplant patients. Primary lung transplant (LTx) recipients received a sirolimus- and tacrolimus-based immunosuppressive therapy immediately after transplantation. Both immunosuppressants were administered with trough level adjusted, while steroid administration was minimized. Four patients were enrolled (2 single-lung transplants, 1 double-lung transplant, 1 heart-lung transplant) in the study. Mean ischemia time was 387 +/- 92 minutes. Acute rejection (at least Grade A1 ISHLT) was detected in 1 patient. Incidence of infection was 0.6 infection per 100 patient-days (3 Aspergillus infections). Until hospital discharge mean sirolimus trough level was 6.2 +/- 1.2 ng/ml. Depending upon mean sirolimus trough levels of each patient, severe wound-healing complications were seen in 3 patients, resulting in bronchial airway dehiscence in 2 patients with lethal outcome in 1 patient. As a result of these complications, we revised the study design after inclusion of only 4 patients: Sirolimus administration is now started after completion of bronchial wound-healing. Sirolimus-based immunosuppressive therapy administered immediately after lung transplantation seems to be associated with severe wound-healing complications of the bronchial anastomosis.     

两剂激素联合两剂达利珠单抗及他克莫司的免疫抑制方案在肝移植中的应用

目的 探讨两剂激素联合两剂达利珠单抗及他克莫司(FK506)的免疫抑制方案在肝移植中应用的安全性及有效性.方法 中山大学附属第一医院器官移植中心2006年9月至2008年3月共实施成人肝移植74例,排除3例血型不合、4例围手术期死亡外,余67例纳人本研究,其中男性54例,女性13例,年龄28～66岁,平均(46.9±8.7)岁.将67例成人肝移植患者随机分为两组:传统免疫抑制方案(激素3个月撤离)组(n=35)和两剂激素免疫抑制方案组(n=32),比较两组术后代谢并发症、感染(含细菌、真菌及巨细胞病毒感染)及排斥反应的发生率的差异.结果 两组患者的术后早期高血糖发生率,高血糖患者使用胰岛素的平均剂量,随访期内糖尿病、高血压及感染的发生率的差异有统计学意义(P<0.05);术后早期高血压发生率及随访期内排斥反应的发生率和高脂血症发生率无明显差异(P0.05).结论 两剂激素的免疫抑制方案是安全有效的,其不增加急性排斥反应的发生率,并可显著减少长期使用激素引起的各种不良反应及并发症的发生.     

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.     

Retinal complications in patients with solid organ or bone marrow transplantations

BACKGROUND: The administration of systemic immunosuppressive agents to recipients of solid organ or bone marrow transplants results in an immunocompromised status. As the number of organ recipients and their life span increase with recent progress in organ transplantation, ocular complications tend to become more diverse and serious. METHODS: From 1995 to 2005, 3656 cases of organ transplantations were performed at Asan Medical Center. The medical records of 1198 of these patients who had been examined at the Department of Ophthalmology were reviewed. RESULTS: Retinal complications were diagnosed in 33 of the transplant recipients; five with bone marrow transplantation, 16 with kidney transplantation, seven with liver transplantation (LT), and five with heart transplantation. Diagnoses included 11 cases of CMV (cytomegalovirus) retinitis, three of acute retinal necrosis, one of progressive outer retinal necrosis, five of fungal chorioretinitis, one of toxoplasmic retinochoroiditis, three of central retinal vein occlusion, and nine of central serous chorioretinopathy. While CMV, fungal, or toxoplasmic chorioretinitis developed frequently in association with extraocular infection or organ rejection, herpetic infection manifested only in the eye without any rejection. Most infectious cases responded well to the standard therapeutic regimen. Interestingly, central retinal vein occlusion developed exclusively following LT, possibly in relation to coagulation cascade abnormality. CONCLUSIONS: To our best knowledge, this comprehensive review presents the largest series of ocular complication in organ transplant recipients. Familiarity with the potential ocular complications as well as a high index of suspicion is warranted to the practicing ophthalmologists.     

Human herpesvirus 6 seronegativity before transplantation predicts the occurrence of fungal infection in liver transplant recipients

BACKGROUND: Invasive fungal infection has a major impact on the morbidity and mortality of liver transplant recipients. Human herpesvirus (HHV)-6 infection after transplantation is associated with an immunosuppressive state and the development of cytomegalovirus disease. Because cytomegalovirus infection is a risk factor for invasive fungal infection after transplantation, we have examined whether HHV-6 and fungal infection are associated after transplantation. METHODS: Pretransplantation sera from 247 consecutive liver transplant recipients were analyzed for IgG to HHV-6. Thirty-three (13%) HHV-6-seronegative recipients were identified. Six of 33 (18%) seronegative recipients experienced fungal infection as compared with 15 of 214 (7%) seropositive recipients (P=0.034). RESULTS: In a univariate analysis of risk factors for fungal infection, pretransplantation seronegativity to HHV-6 (P=0.034), intraoperative cryoprecipitate requirements greater than the 75th percentile (P=0.035), reoperation (P=0.005), biliary stricturing postoperatively (P=0.046), and gastrointestinal or vascular complications postoperatively (P=0.030) were identified as significant risk factors. Moreover, in pairwise multivariate analysis, pretransplantation HHV-6 seronegativity remained a significant variable even in the presence of each of the other variables. CONCLUSIONS: These results suggest that HHV-6 seronegativity before transplantation is a valuable clinical marker that identifies patients at risk for developing fungal infection after transplantation.     

A retrospective analysis of the use of caspofungin in recipients of liver transplant with a modified high index of suspicion for fungal infection. A critical review of mortality,acute cellular rejection,infections, and changes in the liver function tests while on caspofungin

Doria C, Bodzin AS, Vaccino S, Daskalakis C, Krawitz S, Ramirez CB. A retrospective analysis of the use of caspofungin in recipients of liver transplant with a modified high index of suspicion for fungal infection. A critical review of mortality, acute cellular rejection, infections, and changes in the liver function tests while on caspofungin.
Clin Transplant 2011: 25: 569–575. © 2010 John Wiley & Sons A/S. Abstract: This study is a retrospective analysis of death, adverse events (AE), fungal infections, and hepatic function among recipients of liver transplantation at high risk of fungal infection who received prophylactic treatment with caspofungin. After reviewing data of 105 patients who had received isolated liver transplant between January 2003 and April 2007, we identified and analyzed 82 high‐risk patients. Post‐transplant patients at high risk for fungal infection are commonly defined by the presence of at least one of the following: (i) re‐transplantation; (ii) re‐operation; (iii) renal dysfunction. However, in our practice, patients are also considered at high risk for developing fungal infections if they present with the following: (iv) fever of unknown origin; (v) hypothermia; (vi) positive random culture for fungus at the time of transplant (bile and/or ascites); (vii) sepsis; (viii) use of vasopressors; (ix) re‐intubation, during the first hospitalization after liver transplant; (x) prolonged intubation (>24 h), and (xi) acute respiratory distress syndrome, until negative fungal cultures are obtained. Exact conditional logistic regression was used to compare the risk of death, AEs, and fungal infections between patients who received caspofungin, other antifungal drugs, and no antifungal drugs. Analyses were then performed with SAS 9.1 (SAS Institute Inc., Cary, NC, USA). Patients were between 27 and 72 yr old (mean = 55), with two‐thirds male and three‐quarters Caucasian. Sixteen patients received caspofungin (11 preventively), and 32 received other antifungal (26 preventively). There were no proven fungal infections among the patients who received caspofungin, three infections among patients who received other antifungal (3/26 = 12%), and 14 infections among patients who were not preventively treated (14/45 = 31%). These infection rates were significantly different across the three groups (p = 0.029), with caspofungin and other antifungal preventive treatment comparable (p = 0.540), and both better than no preventive treatment at all (OR = 0.15, p = 0.049, for caspofungin versus no preventive treatment; OR = 0.29, p = 0.085, for other antifungal versus no preventive treatment). Caspofungin appears to be an effective preventive agent against fungal infections when used in recipients of liver transplant designated as high risk for fungal infection. Usage of caspofungin in these patients does not carry an apparent increase in risk of death or acute cellular rejection, although we observed a significantly higher risk of AEs, especially acute renal failure (p = 0.001), in patients who received this agent.