Current views on chronic rejection after lung transplantation

Chronic lung allograft dysfunction (CLAD) was recently introduced as an overarching term mainly to classify patients with chronic rejection after lung transplantation, although other conditions may also qualify for CLAD. Initially, only the development of a persistent and obstructive pulmonary function defect, clinically identified as bronchiolitis obliterans syndrome (BOS), was considered as chronic rejection, if no other cause could be identified. It became clear in recent years that some patients do not qualify for this definition, although they developed a chronic and persistent decrease in FEV₁, without another identifiable cause. As the pulmonary function decline in these patients was rather restrictive, this was called restrictive allograft syndrome (RAS). In the present review, we will further elaborate on these two CLAD phenotypes, with specific attention to the diagnostic criteria, the role of pathology and imaging, the risk factors, outcome, and the possible treatment options.     

Cyclophosphamide rescue therapy for chronic rejection after lung transplantation.

BACKGROUND: Obliterative bronchiolitis remains the leading cause of late mortality after heart-lung and lung transplantation. Although several treatment options have been advocated, none has proven to be very successful. Cyclophosphamide is effective in the treatment of idiopathic pulmonary fibrosis, and chronic rejection after lung transplantation is also a fibroproliferative process. We therefore conducted an open, uncontrolled study to look at the effect of cyclophosphamide rescue therapy in the treatment of chronic rejection in lung transplant recipients. METHODS: Between October 1996 and March 1998 cyclophosphamide was prescribed to 7 patients with chronic and persistent rejection who failed to respond to conventional therapy (pulse steroids or antilymphocyte products or both). RESULTS: Cyclophosphamide therapy was initiated on postoperative day 478+/-366. At that time 2 patients were in bronchiolitis obliterans syndrome stage 0, 3 patients in stage 1, and 2 patients in stage 2. Their best postoperative forced expiratory volume in one second (FEV1) was 2.19+/-0.75 L. Three months before the start of cyclophosphamide the FEV1 had declined to 1.90+/-0.83 L, with a further decline to 1.63+/-0.64 L at the time of initiating cyclophosphamide. In 6 of the 7 patients the FEV1 stabilized or increased after cyclophosphamide had been started (mean FEV1 3 and 6 months after cyclophosphamide of 1.77+/-0.58 L and 1.79+/-0.48 L, respectively). One patient died 18 months after the introduction of cyclophosphamide due to progressive obliterative bronchiolitis. In one patient cyclophosphamide had to be stopped because of persistent leucopenia. CONCLUSIONS: Cyclophosphamide might be a promising therapeutic alternative for the treatment of chronic persistent rejection after lung transplantation.     

Donor brain death aggravates chronic rejection after lung transplantation in rats

BACKGROUND: Many recipients of lung transplants from brain-dead donors develop bronchiolitis obliterans, a manifestation of chronic rejection. It has been shown that brain death increases inflammatory mediators and accelerates acute rejection in kidney, liver, and heart transplants. In this study, the authors investigated the hypothesis that brain death increases inflammatory mediators in the donor lung and subsequently aggravates chronic rejection of the lungs after transplantation in rats. METHODS: Brain death was induced in F344 rats by inflation of a subdurally placed balloon catheter. After 6 hr, donor lungs were assessed for influx of leukocytes, expression of cell adhesion molecules, and cytokine mRNA expression. For assessment of the lung after transplantation, lungs from brain-dead F344 rats were transplanted into WKY rats. Lung function after transplantation was monitored by chest radiographs during an observation period of 100 days. At the end of this period, the lungs were histologically examined; also, cytokine mRNA expression was measured. Lungs from ventilated living donors and living donors served as controls. RESULTS: After 6 hr of brain death, influx of polymorphonuclear cells and macrophages and expression of vascular cell adhesion molecule-1 in the donor lungs was increased. After transplantation at postoperative day 100, the lung function was significantly decreased compared with allografts from living donors. In the lung allografts from brain-dead donors, histologic symptoms of chronic rejection were obvious, including severe intimal hyperplasia but without bronchiolitis obliterans. Interleukin-2 mRNA was significantly increased in allografts from brain-dead donors compared with living donors. CONCLUSIONS: This study shows that brain death induces an inflammatory response in the donor lung and subsequently aggravates chronic rejection after transplantation. This may explain the clinical difference in long-term function between lungs from cadaveric donors and living donors.     

Fulminant hyperacute rejection after unilateral lung transplantation

Hyperacute rejection (HAR) is a well-known complication in renal and cardiac transplantation, but rare in lung recipients. We present a case of HAR of the lung graft with a fatal outcome of a male patient with preformed class II anti-HLA antibodies.     

大鼠肢体移植急性排斥反应动物模型的比较研究

目的 探讨建立更简便有效的大鼠肢体移植急性排斥反应动物模型.方法 以Wistar大鼠为供体,SD大鼠为受体,将Wistar大鼠的后侧(左侧或右侧)肢体移植给SD大鼠.实验分成两组,传统术式组:离断SD大鼠原有后侧肢体,将Wistar大鼠同侧肢体通过固定骨骼、吻合血管神经、缝合肌肉皮肤的方法移植给SD大鼠;改进术式组:保留SD大鼠原有后侧肢体,将供体Wistar大鼠的后侧肢体按照左肢配右肢或右肢配左肢的原则,通过缝合皮肤和肌肉的方法固定于SD大鼠后侧肢体的内侧,只吻合股动、静脉,不吻合神经、血管,不固定骨骼.记录两种模型的手术时间、手术前后的体重改变,术后显微外科常规护理,记录移植后宿主饮食量、体重变化、观察移植物变化、手术成功率.结果 两种肢体移植模型各50例,74例成活,移植物排斥反应再现稳定,生存时间均为(14±2)d.传统组和改进组的手术时间分别为(125±40)min、(70±21)min,手术前后平均体重减少量分别为(3.78±1.09)g、(2.05±0.90)g.术后3 d左右,改进组大鼠体重开始增加,传统组1周内体重均持续减少.手术成功率传统组为38%,改进组为90%.在以上4个方面,改进组明显优于传统组(P<0.05).结论 改良术式具有操作简单,成功率高,手术时间短,对大鼠创伤小,大鼠恢复快,值得借鉴和推广.     

Risk factors for chronic rejection after pediatric liver transplantation

BACKGROUND: Chronic rejection is a major cause of graft failure and a frequent reason for retransplantation after pediatric liver transplantation. Identification of risk factors for chronic rejection in pediatric transplant recipients is vital to understanding the pathogenesis of chronic rejection and may help prevent further graft loss. METHODS: The study population consisted of 285 children with 385 liver transplants performed at University of Chicago between 1991 and 1999. Logistic regression analysis was used to evaluate risk factors for chronic rejection, including age, sex, race, type of graft (living related vs. cadaveric), native liver disease, acute rejection episodes, cytomegalovirus (CMV) infection, and posttransplant lymphoproliferative disease (PTLD). RESULTS: The chronic rejection rate was significantly lower in recipients of living-related grafts than in recipients of cadaveric grafts (4% vs. 16%, P=0.001). African-American recipients had a significantly higher rate of chronic rejection than did Caucasian recipients (26% vs. 8%, P<0.001). Numbers of acute rejection episodes, transplantation for autoimmune disease, occurrence of PTLD, and CMV infection were also significant risk factors for chronic rejection. However, recipient age, gender, donor-recipient gender mismatch, and donor-recipient ethnicity mismatch were not associated with higher incidence of chronic rejection CONCLUSION: We have identified a number of risk factors for chronic rejection in a large group of pediatric liver allograft recipients. We believe that donor-recipient matching for gender or race is not likely to reduce the incidence of chronic rejection. The elucidation of the mechanisms by which living-related liver transplantation affords protection against chronic rejection may provide insight into the immunogenetics of chronic rejection and help prevent further graft loss.     

Hyperacute rejection after single lung transplantation: a case report

Hyperacute rejection is a well-known complication in kidney and heart transplantations. However, its occurrence in lung transplantation is extremely rare, with only 4 cases previously described. A 53-year-old female patient blood type O with end-stage chronic obstructive pulmonary disease underwent left lung transplantation. She had 2 negative pretransplantation evaluations for panel-reactive antibodies. One hour after the vascular clamps were released, progressive hypoxia developed. Fiberoptic bronchoscopy revealed an optimal bronchial anastomosis; an abundant pink frothy fluid was observed on the allograft side. Chest X ray sevealed a completely opacified left lung. Due to the low-compliance of the transplanted lung and the risk for native lung hyperinsufflation, independent mechanical ventilation was employed. Despite all measures, multiple organ failure developed and the patient died 24 hours after the procedure. A necropsy evaluation for confirmed the patency of all anastomoses and no signs of ischemia. Retrospectively, a new evaluation for panel-reactive antibodies was performed, with 24% reactivity. Complement-dependent cytotoxicity crossmatch was negative, however, a flow cytometric analysis was positive for both HLA-I (56%) and HLA-II (45%). Further investigation detected an anti-A2 in the recipient serum and the donor had an A2 antigen. Hyperacute rejection is a rare posttransplantation complication highlighted by its precocity and lethality. With the increased number of lung transplantations performed yearly, it is believed that its incidence will also rise. Therefore, prompt diagnosis and familiarity with management strategies are fundamental.     

大鼠慢性主动脉血管移植排斥反应模型的建立

目的 建立一种大鼠慢性主动脉血管移植排斥反应模型.方法 以雄性Lewis鼠为供者,雌性Brown Norway鼠(BN鼠)为受者建立移植模型,截取Lewis鼠胸主动脉1.5 cm,移植于BN鼠腹主动脉段行端端吻合.术后1周每天量体重,观察有无弓背、掉毛、腹泻、精神萎靡等症状,术后第2周起改为每周观察一次,术后8周取移植血管行病理切片、苏木精-伊红(HE)染色及免疫组化检查,观察血管内膜增厚情况及管壁上CD3、CD68、α-actin表达.结果 所有手术均于2h内完成,围手术期死亡数为零.所有的受鼠均存活超过8周.术后受鼠出现弓背、掉毛、体重减轻等症状,第4、5天体重开始回升,1周后基本恢复至术前水平.术后56 d取移植血管,病理切片可见血管内膜较未移植血管明显增厚,免疫组化可见管壁出现大量棕黄色CD3、CD68、α-actin表达阳性细胞.结论 移植后的血管血管内膜明显增厚,管壁上出现大量CD3、CD68、α-actin表达阳性细胞均为慢性排斥反应表现,表明该法建立的大鼠主动脉血管移植模型可为研究慢性排斥反应的发生、进展和干预治疗提供良好的平台.     

The need for lung transplantation in The Netherlands

The aim of this study was to assess the future need for lung transplantation in the Netherlands in the absence of limiting factors, such as a shortage of donor organs. The need was estimated using two different methods. In method 1, estimation of the need was based on data from the Dutch lung transplantation program, collected during a 4-year period (1 April 1992 until 31 March 1996). In method 2, the need was estimated using national mortality data over a 5-year period (1987–1991) preceding the start of the Dutch lung transplantation program. The results of both methods were corrected for known factors of distortion. The number of lung transplantations needed in the Netherlands in the future was estimated to range from 50 to 80 a year, which corresponds to 3.2–5.2 transplantations per million inhabitants per year. Considering the current supply of donor lungs in the Netherlands, only about one-third of the patients in need of a lung transplant in the future will be able to receive one. Received: 5 March 1997 Received after revision: 22 May 1997 Accepted: 9 July 1997     

The impact of first untreated subclinical minimal acute rejection on risk for chronic lung allograft dysfunction or death after lung transplantation

Acute cellular rejection (ACR) is a significant risk factor for chronic lung allograft dysfunction (CLAD). Although clinically manifest and higher grade (≥A2) ACR is generally treated with augmented immunosuppression, management of minimal (grade A1) ACR remains controversial. In our program, patients with subclinical and spirometrically stable A1 rejection (StA1R) are routinely not treated with augmented immunosuppression. We hypothesized that an untreated first StA1R does not increase the risk of CLAD or death compared to episodes of spirometrically stable no ACR (StNAR). The cohort was drawn from all consecutive adult, first, bilateral lung transplantations performed between 1999 and 2017. Biopsies obtained in the first‐year posttransplant were paired with (forced expiratory volume in 1 second FEV₁). The first occurrence of StA1R was compared to a time‐matched StNAR. The risk of CLAD or death was assessed using univariable and multivariable Cox proportional hazards models. The analyses demonstrated no significant difference in risk of CLAD or death in patients with a first StA1R compared to StNAR. This largest study to date shows that, in clinically stable patients, an untreated first A1 ACR in the first‐year posttransplant is not significantly associated with an increased risk for CLAD or death. Watchful‐waiting approach may be an acceptable tactic for stable A1 episodes in lung transplant recipients.     

The significance of a single episode of minimal acute rejection after lung transplantation

BACKGROUND: Bronchiolitis obliterans syndrome (BOS) remains the leading obstacle to better long-term outcomes after lung transplantation. Acute rejection has been identified as the primary risk factor for BOS, but the impact of minimal acute rejection, especially a solitary episode, has usually been discounted as clinically insignificant. METHODS: We performed a retrospective cohort study of 259 adult lung transplant recipients to determine the risk of BOS associated with a single episode of A1 rejection, without recurrence or subsequent progression to a higher grade. The cohort was divided into 3 groups based on the severity of acute rejection (none, single episode of A1, and single episode of A2). We determined the risks of BOS stages 1, 2, 3, and death for each group using univariate and multivariate Cox regression analyses. RESULTS: A solitary episode of A1 rejection was a significant risk factor for BOS stages 1 and 2, but not stage 3 or death, in the univariate analysis. Multivariate Cox regression models confirmed that the risk of BOS attributable to a single episode of A1 rejection was independent of other potential risk factors, such as community acquired respiratory viral infections, number of HLA mismatches, and cytomegalovirus pneumonitis. Likewise, univariate and multivariate analyses demonstrated that a single episode of A2 rejection was a significant risk factor for all stages of BOS but not death. CONCLUSIONS: A single episode of minimal acute rejection without recurrence or subsequent progression to a higher grade is a significant predictor of BOS independent of other risk factors.     

Rat cytomegalovirus and Listeria monocytogenes infection enhance chronic rejection after allogenic rat lung transplantation

The role of infection in the pathomechanism of obliterative bronchiolitis (OB) after human lung transplantation is controversial. In a rat lung transplantation model, we analyzed the effect of viral [rat cytomegalovirus (RCMV)] and bacterial infection [Listeria monocytogenes (LM)] on the development of chronic allograft rejection. Fisher rats underwent single left lung transplantation with allografts from Lewis rats. Postoperatively, animals were infected with either RCMV or LM, or served as noninfected controls. Animals were killed on day 120 and both lungs were evaluated histopathologically for chronic airway and chronic vascular rejection. Infection with RCMV produced a significant increase in the incidence of chronic airway rejection (66.7% vs. 20%), compared with noninfected long-term surviving animals. In rats with bacterial infection (LM) a similar increase of chronic airway changes as in viral infection (50% vs. 20%) was observed. Chronic rejection of allografts infected with either RCMV or LM was associated with significantly enhanced expression of intercellular adhesion molecule-1 (ICAM-1) on the endothelium. More infiltrating leukocytes (CD18, CD11a, CD44) and ED1-positive macrophages were found in allografts of infected animals. In this experimental model of chronic airway rejection in long-term surviving rats, not only viral but also bacterial infection resulted in enhanced development of chronic airway and vascular rejection. These results support our hypothesis that infectious complications have a substantial influence on the development of OB in human lung allografts.     

Organ changes and bacterial translocation in a rat model of chronic rejection after small bowel transplantation

Rejection after small bowel transplantation (SBTx) may allow bacterial translocation damaging the liver and lungs. This study investigated these issues in a rat model of chronic rejection. MATERIALS AND METHODS: Orthotopic SBTx was performed in syngeneic (SYN) (ACI-ACI, n=8) and allogeneic (ALLO) (ACI-Lewis, n=8) rat strain combinations. Cyclosporine was given to ALLO rats for 28 days. Animals were sacrified between 55 and 65 days. Lymph nodes and venous samples were cultured; Escherichia coli DNA was assessed by polymerase chain reaction. We measured intestine, liver, spleen, and lung protein and DNA contents. Chronic rejection was histologically confirmed. RESULTS: Two of eight and four of eight rats died in the first week after SYN and ALLO SBTx, respectively. There were no differences in organ weights or DNA and protein contents compared with the controls. Gram-negative enteric bacteria were found in two of four ALLO and two of six SYN rats (ns), and aerobic gram-positive were found in two of four and two of six (ns), respectively. Anaerobic growth occurred in mesenteric lymph nodes in only one ALLO rat. E. coli DNA was negative in all animals. Lungs were severely emphysematous in ALLO rats with no histologic changes observed in the other phagocytic organs. Mild rejection was found in the intestine of ALLO rats. CONCLUSIONS: Bowel lesions in ALLO rats might be consistent with chronic rejection and lung lesions could be related to bacterial translocation after SBTx. However, contrary to our expectations, no significant bacterial translocation was demonstrated in either group at the end of the experiments.