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.
Bosentan (an oral dual endothelin receptor antagonist) improves symptoms and cardiac hemodynamics and reduces clinical worsening in patients with pulmonary arterial hypertension (PAH). The VITAL ...study assessed the effect of bosentan on quality of life in patients with WHO Functional Class III or IV PAH (idiopathic or associated with connective tissue diseases).
Quality of life was assessed prospectively using the MOS SF-36 and AQOL questionnaires. Baseline readings and scores at 3 and 6 months were collected, in addition to other efficacy and safety data.
Among the 177 study patients, SF-36 scores were significantly improved at 3 months in the domains of physical functioning (27.3 to 34.8; p < 0.0001), role-physical (16.6 to 30.9; p < 0.0001), vitality (35.2 to 41.1; p = 0.0003), social functioning (48.0 to 58.6; p < 0.0001), mental health (64.2 to 72.0; p = 0.005) and role-emotional (44.8 to 58.1; p = 0.001). Improvements were seen in all etiologic sub-groups and were maintained in patients who remained on bosentan. An improvement in AQOL measures at 3 months was also noted for patients with baseline WHO Functional Class III.
Bosentan significantly improves quality of life in patients with idiopathic PAH or PAH associated with connective tissue diseases.
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.
Background. Airway complications are a significant cause of morbidity after lung transplantation. Effective treatment reduces the impact of these complications.
Methods. Data from 123 lung (99 ...single, 24 bilateral) transplants were reviewed. Potential risk factors for airway complications were analyzed. Stenoses were treated with expanding metal (Gianturco) stents.
Results. Mean follow-up was 749 days. Thirty-five complications developed in 28 recipients (complication rate: 23.8%/anastomosis). Mean time to diagnosis was 47 days. Only Aspergillus infection and airway necrosis were significantly associated with development of complications (
p < 0.00001 and
p < 0.03, respectively). Stenosis was diagnosed an average of 42 days posttransplant. Average decline in forced expiratory volume in 1 second (FEV
1) was 39%. Eighteen patients (13 single and 5 bilateral) required stent insertion. Mean increase in FEV
1 poststenting was 87%. Two stent patients died from infectious complications. Six patients required further intervention. Long-term survival and FEV
1 did not differ from nonstented patients.
Conclusions. Aspergillus and airway necrosis are associated with the development of airway complications. Expanding metal stents are an effective long-term treatment.
The 6-minute walk distance (6MWD) is a widely used clinical indicator of exercise capacity. Although used as part of the assessment process in determining a candidate's suitability for lung ...transplantation (LT), the literature describing the impact of the 6MWD in predicting survival on LT waiting lists is limited. This study aimed to determine the hazard function associated with the 6MWD, and its utility relative to other prognostic variables.
A retrospective chart review was conducted on 163 patients who were listed for single or double LT, and either survived to transplant or died while on the waiting list. A Cox regression for survival analysis, stratified by diagnostic group, was conducted utilizing the 6MWD, demographic variables and measures of cardiopulmonary function.
The 6MWD proved to be the only significant covariate in the Cox regression for survival analysis (p < 0.001), with all other variables eliminated as non-significant. Furthermore, there was a protective effect for each unit increase in the 6MWD Exp (B) = 0.994, 95% confidence interval 0.990 to 0.997.
This research demonstrates that the 6MWD is useful for stratifying patients on the LT waiting list by identifying those patients with a significantly higher risk of mortality.
Background. Heart-lung transplantation (HLT) for Eisenmenger syndrome (ES) provides superior early and intermediate survival when compared with other forms of transplantation. The early risk factors ...and long-term outcome of HLT for ES are less well defined.
Methods. We analyzed 263 patients who had undergone HLT at our institution during more than 15 years. Fifty-one consecutive patients with ES who underwent HLT, 33 (65%) of which had simple anatomy, were compared with 212 cases having HLT for other indications (non-ES).
Results. Female sex and previous thoracotomy were more prevalent in the ES group. Patients with ES had greater postoperative blood loss and returned more frequently to the operating room for control of bleeding. There were 8 (16%) early deaths in the ES group compared with 27 (13%) in non-ES (
p = 0.65). One-, 5-, and 10-year survival rates for ES were 72.6%, 51.3%, and 27.6%, respectively, compared with non-ES of 74.1%, 48.1%, and 26.0%, respectively, and there was no difference in survival overall (
p = 0.54). Among ES patients, previous thoracotomy was a risk factor for hospital death. A subgroup analysis based on simple versus complex type of ES did not show statistically significant differences in terms of postoperative course or early or late survival.
Conclusions. Heart-lung transplantation is a successful procedure for ES. Despite a greater frequency of risk factors and a more difficult operative course, early and late outcome with HLT is comparable to non-ES recipients.
Parvovirus B19 (PVB) is a non-enveloped, single-stranded DNA virus of the Parvoviridae family pathogenic to humans. Despite numerous case reports of pure red cell aplasia in lung transplant (LT) ...recipients after PVB infection, the epidemiology remains poorly outlined. Over a 3-year period, 3 of 54 LT patients with unexplained anemia tested positive for circulating PVB by a nested polymerase chain reaction (PCR) assay. All of these patients presented with anemia and leukopenia, with a favorable long-term prognosis.
Background and objective: Bosentan, an oral, dual endothelin receptor antagonist, significantly improves functional status, haemodynamic measures and survival in patients with pulmonary arterial ...hypertension (PAH). However, there are limited data on the effect of bosentan on quality of life (QOL) and its relationship to changes in functional status, as measured by the 6 minute walk distance (6MWD).
Methods: A retrospective analysis was performed of a large, open‐label, multicentre trial (VITAL) of bosentan in patients with PAH. Data for 6MWD were collected at baseline, 3 or 6 months and these results were correlated with QOL measurements collected as part of the assessment of patients enrolled in the trial.
Results: Sixty‐nine patients with PAH (mean age 52 years) who were enrolled in the trial had valid QOL (SF‐36) measurements and 6MWD data that could be retrieved from clinical notes. At 3 and 6 months, bosentan therapy improved 6MWD compared with baseline (49.5 m and 47.2 m, respectively, P < 0.001) as well as QOL domains, with a significant correlation between these two markers on cross‐sectional analysis. However, there was a poor relationship when comparing changes in 6MWD with changes in QOL, in response to therapy.
Conclusion: Bosentan therapy was associated with improvements in QOL and 6MWD for at least 6 months. At all measured time points, there was a close correlation between 6MWD and most QOL domains. QOL is an important parameter and should be considered as part of the standard assessment for any trial investigating therapy in PAH.
In Australia, no therapeutic agents were subsidised for the treatment of idiopathic pulmonary artery hypertension (iPAH), a rare progressive and severe disease with short life expectancy, until 1 ...March 2004, when bosentan (a dual endothelin receptor antagonist of high cost) was listed on the Pharmaceutical Benefits Scheme (PBS). Bosentan, in addition to conventional therapy, has been shown to slow iPAH progression and improve clinical and haemodynamic status and symptomatology, compared with placebo and conventional therapy. The objective of this paper is to describe the process of the Australian Pharmaceutical Benefits Scheme listing for bosentan (Tracleer), which included a health economic model assessing the cost effectiveness of bosentan from a healthcare payer perspective, and a risk-sharing arrangement based on the establishment of a patient registry.
The health economic model predicted the cost, hospitalisation and mortality rates of a population of iPAH patients treated with either the conventional therapy regimen used in Australia or bosentan plus the conventional therapy regimen. The model was implemented as a first-order Monte Carlo simulation with mortality modelled directly as the main clinical outcome. The impacts of proposed continuation criteria, restricting the ongoing use of the drug, were evaluated. Costs and outcomes were discounted at 5% and a sensitivity analysis examined the robustness of the key assumptions.
The model predicted that after 5, 10 and 15 years, the difference in average cumulative costs between bosentan plus conventional therapy and conventional therapy alone would be 116,929 Australian dollars (A dollars), A181,808 dollars and A216,331 dollars for each patient, respectively. There would be an associated increase in average life expectancy of 1.39, 2.93 and 3.87 years at 5, 10 and 15 years, respectively, with an incremental cost-effectiveness ratio at 15 years of A55,927 dollars for each life-year gained. Removing the continuation criteria from the model increased the incremental cost-effectiveness ratio to A62,267 dollars (1996-2002 values).
Economic modelling based on improved survival suggests bosentan to be a potentially cost-effective treatment for iPAH. However, the structure of the model and its inputs should be reviewed and updated as more data become available.
The objective of this study was to report the outcome of pulmonary endarterectomy (PEA) surgery performed for chronic thromboembolic pulmonary hypertension (CTEPH) at a single tertiary center. The ...prospective study consisted of 35 patients with surgically amenable CTEPH undergoing PEA between September 2004 and September 2010. The main outcome measures were Functional (New York Heart Association NYHA class, 6-Minute Walk Distance), hemodynamic (echocardiography, right heart catheterization, and cardiac MRI), and outcome data (morbidity and mortality). Following PEA, there were significant improvements in NYHA class (pre 2.9±0.7 vs. post 1.3±0.5, P < 0.0001), right ventricular systolic pressure (pre 77.4±24.8 mmHg vs. post 45.1±24.9 mmHg, P = 0.0005), 6-Minute Walk Distance (pre 419.6±109.4 m vs. post 521.6±83.5 m, P = 0.0017), mean pulmonary artery pressure (pre 41.8±15.3 mmHg vs. post 24.7±8.8 mmHg, P = 0.0006), and cardiac MRI indices (end diastolic volume pre 213.8±49.2 mL vs. post 148.1±34.5 mL, P < 0.0001; ejection fraction pre 40.7±9.8 mL vs. post 48.1±8.9 mL, P = 0.0069). The mean cardiopulmonary bypass time was 258.77±26.16 min, with a mean circulatory arrest time of 43.83 ±28.78 min, a mean ventilation time of 4.7±7.93 days (range 0.2–32.7), and a mean intensive care unit stay of 7.22±8.71 days (range 1.1–33.8). Complications included reperfusion lung injury (20%), persistent pulmonary hypertension (17.1%), slow respiratory wean (25.7%), pericardial effusion (11.4%), and cardiac tamponade (5.7%). 1-year mortality post-procedure was 11.4%. Pulmonary endarterectomy can be performed safely with relatively low mortality.
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