In 1990, an international grading scheme for the grading of pulmonary allograft rejection was adopted by the International Society for Heart and Lung Transplantation (ISHLT) and was modified in 1995 ...by an expanded group of pathologists. The original and revised classifications have served the lung transplant community well, facilitating communication between transplant centers with regard to both patient management and research. In 2006, under the direction of the ISHLT, a multi-disciplinary review of the biopsy grading system was undertaken to update the scheme, address inconsistencies of use, and consider the current knowledge of antibody-mediated rejection in the lung. This article summarizes the revised consensus classification of lung allograft rejection. In brief, acute rejection is based on perivascular and interstitial mononuclear infiltrates, Grade A0 (none), Grade A1 (minimal), Grade A2 (mild), Grade A3 (moderate) and Grade A4 (severe), as previously. The revised (R) categories of small airways inflammation, lymphocytic bronchiolitis, are as follows: Grade B0 (none), Grade B1R (low grade, 1996, B1 and B2), Grade B2R (high grade, 1996, B3 and B4) and BX (ungradeable). Chronic rejection, obliterative bronchiolitis (Grade C), is described as present (C1) or absent (C0), without reference to presence of inflammatory activity. Chronic vascular rejection is unchanged as Grade D. Recommendations are made for the evaluation of antibody-mediated rejection, recognizing that this is a controversial entity in the lung, less well developed and understood than in other solid-organ grafts, and with no consensus reached on diagnostic features. Differential diagnoses of acute rejection, airway inflammation and chronic rejection are described and technical considerations revisited. This consensus revision of the working formulation was approved by the ISHLT board of directors in April 2007.
Renal transplantation is the optimal treatment for selected patients with end-stage renal disease (ESRD). However, the survival benefit of renal transplantation among patients with ESRD attributed to ...granulomatosis with polyangiitis (GPA) is unknown.
We identified patients from the United States Renal Data System with ESRD due to GPA (ESRD-GPA) between 1995 and 2014. We restricted our analysis to waitlisted subjects to evaluate the impact of transplantation on mortality. We followed patients until death or the end of follow-up. We compared the relative risk (RR) of all-cause and cause-specific mortality in patients who received a transplant versus non-transplanted patients using a pooled logistic regression model with transplantation as a time-varying exposure.
During the study period, 1525 patients were waitlisted and 946 received a renal transplant. Receiving a renal transplant was associated with a 70% reduction in the risk of all-cause mortality in multivariable-adjusted analyses (RR=0.30, 95% CI 0.25 to 0.37), largely attributed to a 90% reduction in the risk of death due to cardiovascular disease (CVD) (RR=0.10, 95% 0.06-0.16).
Renal transplantation is associated with a significant decrease in all-cause mortality among patients with ESRD attributed to GPA, largely due to a decrease in the risk of death to CVD. Prompt referral for transplantation is critical to optimise outcomes for this patient population.
We report our initial experience with three patients who received heart-lung transplants. The primary immunosuppressive agent used was cyclosporin A, although conventional drugs were also ...administered. In the first patient, a 45-year-old woman with primary pulmonary hypertension, acute rejection of the transplant was diagnosed 10 and 25 days after surgery but was treated successfully; this patient still had normal exercise tolerance 10 months late. The second patient, a 30-year-old man, underwent transplantation for Eisenmenger's syndrome due to atrial and ventricular septal defects. His graft was not rejected, and his condition was markedly improved eight months after surgery. The third patient, a 29-year-old woman with transposition of the great vessels and associated defects, died four days postoperatively of renal, hepatic, and pulmonary complications. We attribute our success to experience with heart-lung transplantation in primates, to the use of cyclosporin A, and to the anatomic and physiologic advantages of combined heart-lung replacement. We hope that such transplants may ultimately provide an improved outlook for selected terminally ill patients with pulmonary vascular disease and certain other intractable cardiopulmonary disorders.
Background: Obliterative bronchiolitis remains the major limitation to long-term survival after lung transplantation. A thorough understanding of the factors that confer high risk of developing ...obliterative bronchiolitis or its physiologic surrogate bronchiolitis obliterans syndrome is important to help define therapeutic strategies.
Methods: We performed a systematic review of studies published since the beginning of 1990. The review excluded non-human studies, publications before 1990, small (less than 25 patients) studies that were predominantly concerned with investigating the pathogenesis of obliterative bronchiolitis, studies solely concerned with diagnosis or treatment of obliterative bronchiolitis, and overlapping studies from the same center. Onset of bronchiolitis obliterans syndrome or obliterative bronchiolitis was the outcome of interest.
Results: Acute rejection plays an important role in obliterative bronchiolitis and bronchiolitis obliterans syndrome onset, and late rejection is a significant risk factor. Lymphocytic bronchitis/bronchiolitis is also a risk factor, with some evidence that late onset is associated with greater risk. The effects of cytomegalovirus, other infectious organisms, and human leukocyte antigen matching are less clear and require further confirmation. There is little evidence that recipient and donor characteristics play a major role.
Conclusions: This systematic review supports the view that obliterative bronchiolitis arises from alloimmunologic injury marked by clinically apparent acute rejection episodes and that inflammatory conditions, including viral infections or ischemic injury, may also play a role. Implications for therapy are discussed.
Cardiac allograft vasculopathy (CAV) is a common cause of death after heart transplantation. Coronary angiography is used to monitor the progress of recipients. Diagnostic accuracy of angiography and ...risk factors for CAV have not been clearly established. Between August 1979 and January 2002, 566 1-year survivors of heart transplantation underwent 2168 angiograms and were classified as having no CAV (0% stenosis), mild-moderate CAV (up to 70% stenosis), or severe CAV (>70% stenosis). We used serial measurements of stenosis to estimate the diagnostic accuracy of angiography and to assess the following risk factors for CAV onset, progression, and survival: recipient and donor age and sex, preoperative ischemic heart disease (IHD), acute rejection rates, cytomegalovirus (CMV) infection, and serologic status. CAV was diagnosed by angiography in 248 of 556 (45%) 1-year survivors, with a mean onset time of 8.6 years. Patients spent a mean of 3.4 years with mild-moderate disease and 3.4 years with severe disease before death. Angiography specificity was 97.8%, and sensitivity was 79.3%. The following variables were found to significantly increase the risk of CAV onset: recipient age relative rate (95% confidence interval) 1.16 (1.01-1.34), donor age by 1.27 (1.13-1.43), male recipient by 2.00 (1.11-2.57), pretransplant IHD by 1.75 (1.30-2.36), cumulative rejection by 1.13 (1.05-1.21), and CMV infection by 1.42 (1.06-1.92). Acute rejection increased risk of death by 1.48 (1.19-1.85). Angiography is highly specific and moderately sensitive for diagnosis of CAV. Risk of CAV onset is related to donor age and recipient history of pretransplant IHD and is further increased by immune-related insults of acute rejection and CMV infection.
Acute rejection increases the inflammatory burden of the transplanted organ and predisposes to cardiac allograft vasculopathy (CAV). In this study we aim to determine the magnitude of the ...association, and to differentiate between the effects of mild vs severe rejection episodes.
Between 1988 and 2003, 489 1-year survivors of heart transplantation underwent 1,435 angiograms. These patients were classified as having no CAV (0% stenosis), mild/moderate CAV (<70%) or severe CAV (>70%). Acute rejection was considered either mild (Grades 1A, 1B and 2 untreated) or moderate/severe (Grade 2 treated on a clinical basis and Grades 3A, 3B and 4). We used multi-state Markov models to examine risk factors for the onset of CAV.
Expressed as relative risk, the onset of CAV was significantly increased by donor age (1.26 per 10 years, 95% confidence interval CI 1.12 to 1.42), male recipient (1.72, 95% CI 1.01 to 2.94), pre-transplant recipient ischemic disease (1.53, 95% CI 1.14 to 2.06) and cumulative number of moderate/severe rejections (1.10 per episode, 95% CI 1.03 to 1.18). Human leukocyte antigen (HLA) and cytomegalovirus (CMV) matching, donor gender, recipient age, smoking, cumulative CMV infections and mild rejections were not significant risk factors. Estimated annual onset rate of CAV was 11.3% for patients with no moderate/severe rejection, rising to 13.6% for those with two and 18.0% for those with five such rejections.
Acute moderate/severe cellular rejection has a cumulative impact on CAV onset, whereas mild, untreated rejection is not associated with CAV.
Background: Lung transplantation has become an established procedure for treating patients with endstage lung disease, resulting in broadening criteria for recipient selection. The survival benefit ...for some patient groups has yet to be established.
Methods: We reviewed 653 patients accepted for lung transplantation at our center. Patients were categorized into 6 diagnosis groups: cystic fibrosis (174), obstructive lung disease (163), pulmonary fibrosis (100), Eisenmenger’s syndrome (76), pulmonary hypertension (68), bronchiectasis (51), and other (21). Using Cox regression, we estimated the time at which early operative risk of death fell below pre-operative risk levels (crossover point) and the point at which early high post-operative risk was offset by later low risk (equity point). The relative benefits of single lung vs double lung/heart-lung transplantation were assessed for patients with obstructive lung disease and pulmonary fibrosis.
Results: Post-operative risk of death fell below pre-operative risk levels for all diagnosis groups, indicating a survival advantage. The equity point was achieved for all distinct diagnosis groups (except Eisenmenger’s); this survival benefit was significant for patients with obstructive lung disease, cystic fibrosis, and pulmonary hypertension. Single lung vs double lung/ heart-lung comparisons showed no significant difference in survival benefit.
Conclusion: All survival benefit patient groups achieve after lung transplantation, with the exception of patients with Eisenmenger’s syndrome, who may have prolonged survival while listed. Differences in survival benefit between single lung and double or heart-lung transplantation are not significant for patients with obstructive lung disease or pulmonary fibrosis.
Bronchiolitis obliterans syndrome (BOS), defined as an irreversible, staged decline in forced expiratory volume in 1 second (FEV
1), is an established marker of obliterative bronchiolitis. Potential ...causes of BOS include sub-clinical chronic rejection and/or exaggerated healing response following acute injury. BOS may thus result from two or more distinct processes, both acute and chronic.
A total of 5,916 measurements of FEV
1 from 204 lung transplant recipients surviving at least 6 months after transplantation were analyzed. Follow-up ranged from 6 months to 13 years. By adjusting for the acute effects of rejection, pulmonary infection and measurement variation on FEV
1 trace, patients either had a linear decline characterized by a single acute drop in FEV
1 of >15% at BOS onset, or a chronic linear decline in FEV
1. The fraction having acute onset was estimated. Acute events occurring within the first 6 months were assessed as risk factors for acute onset BOS.
Of the 204 patients, 8% died before BOS onset and 18% were BOS-free at analysis. For 18% of patients, BOS onset followed a chronic linear decline in FEV
1 of 3.7% per year, with a median time of BOS onset >99 months. For 56% of patients, BOS onset followed an acute drop in FEV
1 of median 33.8% (95% CI 19.1% to 39.7%), with median onset time of 52 months. During the first 6 months, acute rejection was significantly and independently associated with acute onset of BOS (relative risk = 1.15 per episode, 95% CI 1.03 to 1.29,
p = 0.01), whereas pulmonary infection and cytomegalovirus (CMV) infection were not. Acute BOS onset followed a documented acute event in the previous 6 months in 38 of 114 (33%) of cases.
BOS likely reflects more than one process. Compared with those who had a slow linear decline in lung function, acute BOS onset was associated with acute rejection in the first 6 months, was often triggered by an acute event and had poor prognosis, with obliterative bronchiolitis (OB) the main cause of death.
This article documents the addition of 111 microsatellite marker loci to the Molecular Ecology Resources Database. Loci were developed for the following species: Acipenser oxyrinchus desotoi, ...Anopheles nuneztovari sensu lato, Asellus aquaticus, Calopteryx splendens, Calopteryx virgo, Centaurea aspera, Centaurea seridis, Chilina dombeyana, Proctoeces cf. lintoni and Pyrenophora teres f. teres.
We have previously reported that prophylaxis for cytomegalovirus (CMV) infection does not influence the incidence of bronchiolitis obliterans syndrome (BOS) at 2 years. The effect of CMV infection ...(without evidence of disease) on BOS is still not well understood. Moreover, the incidence and risk factors for development of BOS in CMV-antibody-negative donor/recipient matches in lung transplantation have not been described. The aim of this study is to determine the incidence of BOS in lung transplant patients with CMV-antibody-negative (−) donors (D) and recipients (R), and to evaluate the risk factors that predispose to BOS in this sub-group.
A retrospective study of data from the transplant database of our center was performed. All single-lung (SL), double-lung (DL) and heart–lung block (HL) transplant patients who survived >2 years post-transplant were included in the study group. They were grouped as follows: D
−/R
−,
n = 102; D
−/R
+,
n = 70; D
+/R
−,
n = 33, and D
+/R
+,
n = 92.
The 3-year BOS-free survival rates were 65%, 56%, 58% and 67%, respectively, and the incidence rates of BOS at 5 years post-transplant in the different groups were 57%, 62%, 78% and 55% (
p > 0.05). In the D
−/R
− group, the significant risk factor for developing BOS was three or more episodes of acute rejection (
p = 0.02). The mean numbers of acute rejection episodes per 100 patients-days within the first 6 months were 1.28, 1.06, 0.50 and 1.11 (
p < 0.001 overall) for the four groups, respectively.
Although CMV is believed to be a risk factor for BOS, its absence did not affect the occurrence or incidence of BOS in lung transplant patients. The main risk factor for BOS in the CMV-antibody-negative population remains the number of acute rejection episodes within the first 6 months after transplantation.
PDF
