Size matching in lung transplantation using predicted total lung capacity.

Height is used in allocation of donor lungs as an indirect estimate of thoracic size. Total lung capacity (TLC), determined by both height and sex, could be a more accurate functional estimation of thoracic size. Size-matching criteria based on height versus predicted TLC was retrospectively evaluated, and, furthermore, whether a TLC mismatch was related to clinical and functional complications. The ratio of donor and recipient height, as well as the ratio of predicted TLC in donors and recipients, were calculated in 80 patients after bilateral lung transplantation. Complications evaluated included persistent atelectasis, persistent pneumothorax and increased number of days in intensive care, occurrence of bronchiolitis obliterans syndrome and limitation of exercise capacity. Median height donor/recipient ratio was 1.01 (0.93-1.12). Median predicted TLC donor/recipient ratio was 1.01 (with a clearly broader range 0.72-1.41). Neither sex mismatch nor TLC mismatch were related to clinical or functional complications. Allocation of donor lungs based upon height alone leads to a substantial mismatch in total lung capacity caused by sex mismatch. The absence of complications suggests that a greater height donor/recipient discrepancy can be accepted for allocation than previously assumed.

Simulated waiting list prioritization for equitable allocation of donor lungs.

BACKGROUND: In lung transplantation (LTx), allocation of donor lungs is usually based on blood group, height and waiting time. Long waiting times favor patients with a slowly progressive end-stage lung disease and make the current allocation system the subject of discussion. In an attempt to equalize the chances for transplantation for every patient, irrespective of diagnosis, we investigated the effect of diagnosis-dependent prioritization on the waiting list, using a simulation model. METHODS: For the main disease categories on the waiting list, the relative risks of dying while on the waiting list were calculated using empirical data from the Dutch LTx program gathered over a period of 10 years. In a microsimulation model of the Dutch LTx program based on data from the actual situation, patients with diagnoses associated with a statistically significant increased risk of death while on the waiting list were prioritized by multiplying the time on the waiting list by the relative risk. RESULTS: Relative risks of death on the waiting list were increased significantly in patients with cystic fibrosis, primary pulmonary hypertension and pulmonary fibrosis. Prioritization resulted in an increased chance of transplantation for the prioritized diagnoses and a decreased chance for the non-prioritized diagnoses. The distribution of diagnoses after LTx was almost equal to the distribution of diagnoses on the waiting list. CONCLUSION: The simulated method of prioritization on the waiting list is a step forward to a more equitable allocation of donor lungs. Moreover, this method is clinically feasible, as long as the waiting list is updated frequently.

Long-term survival despite early loss of graft function after single lung transplantation for pulmonary fibrosis.

We report a patient who received a single, left lung transplantation for idiopathic pulmonary fibrosis. The effect of the graft on pulmonary improvement was only temporary, because the patient developed obliterative bronchiolitis (OB), resulting in complete destruction of the graft. The patient, however, remains alive 6 years after OB was diagnosed, apparently as a consequence of native lung improvement with triple-immunosuppressive medicine. This case is of interest for several reasons: first, it shows that pulmonary fibrosis may respond to intensive immunosuppressive therapy; second, it demonstrates that ventilation scintigraphy is useful in addition to pulmonary function tests in estimating the actual function of the graft after single lung transplantation; and third, it appears that the gradation of bronchiolitis obliterans syndrome (BOS) after single lung transplantation may overestimate the true function of the transplant.

Extracorporeal membrane oxygenation before induction of anesthesia in critically ill thoracic transplant patients.

Cardiorespiratory failure just before surgery in critically ill thoracic transplant patients can have catastrophic consequences. We judged the cardiorespiratory condition in three of 160 thoracic transplant procedures performed in our center too unstable for a safe induction of anesthesia. In these 3 patients, extracorporeal membrane oxygenation support was installed before induction of anesthesia to maintain an adequate cardiorespiratory state. This strategy was successful for all 3 patients, and long-term survival was achieved with a good quality of life. Guidelines for indications to follow this strategy are discussed.

Long-term outcome of lung transplantation is predicted by the number of HLA-DR mismatches.

BACKGROUND: The importance of HLA mismatch in determining long-term outcome in lung transplantation remains largely uncertain. METHODS: A retrospective analysis of 102 consecutive primary lung transplants was performed to identify risk factors for poor long-term outcome after lung transplantation defined as graft survival and bronchiolitis obliterans syndrome (BOS) stage I and II. Variables included were patient characteristics (age, sex, prior diagnosis), the number of HLA mismatches between donor and recipient, cold ischemic time, cytomegalovirus serologic concordance, number of acute rejections, and time to first rejection. Variables carrying significance in a univariate analysis were subjected to a proportional hazard regression analysis. RESULTS: In the multivariate analysis, an increased number of acute rejections correlated positively with decreased graft survival (risk ratio [RR] = 1.25; 95% confidence interval [CI], 1.05-1.5; P = 0.011), development of BOS stage I (RR = 1.36/episode; 95% CI, 1.16-1.58;P < 0.001), and BOS stage II (RR = 1.42/episode; 95% CI, 1.2-1.67; P < 0.001). An increased time to rejection correlated positively with reduced graft survival (RR = 1.03/day; 95% CI, 1.01-1.06; P = 0.02), and BOS stage I and II (both RR = 1.04/day; 95% CI, 1.01-1.07; P < 0.005). Compared with 2 HLA-DR mismatches, 0 or 1 mismatch was associated with improved graft survival (RR = 0.43; 95% CI, 0.19-0.98; P = 0.045) and protected against development of BOS stage I (RR = 0.47; 95% CI, 0.23-0.98; P = 0.044) and BOS stage II (RR = 0.35; 95% CI, 0.15-0.83; P = 0.017). CONCLUSIONS: HLA-DR mismatching appears to be a risk factor for the development of BOS and graft loss. Improved outcome after lung transplantation might be achieved with prospective matching for HLA-DR. Alternatively, the amount and type of immunosuppressive drugs may be guided by the degree of HLA-DR (mis)matching.

Gastrointestinal complications in lung transplant survivors that require surgical intervention.

BACKGROUND: Lung transplantation is widely accepted as a treatment for end-stage lung disease. At present, information regarding the incidence and outcome of acute gastrointestinal complications in lung transplant survivors is limited. METHODS: Since 1990, 127 lung transplantations have been performed in 125 patients: 73 males (58 per cent) and 52 females (42 per cent) of median age 43 (range 9-64) years. Patients received a standard induction and maintenance regimen of immunosuppression. RESULTS: At a median follow-up of 2.6 (range 0-8.6) years the overall survival rate was 68 per cent. An acute abdomen requiring surgical intervention was diagnosed in 12 patients (10 per cent). The median time following lung transplantation was 19 (range 3-68) months. Eight cases of bowel perforation, two of appendicitis, one of colitis, one of cholecystitis, and one pneumoperitoneum were encountered. Four Hartmann procedures, two sigmoid resections, one small bowel resection, two appendicectomies, a subtotal colectomy, a cholecystectomy and an exploratory laparotomy were performed with minimal morbidity and no postoperative death. CONCLUSION: Lung transplant survivors are at increased risk of developing an acute abdomen because of the use of high-dose immunosuppressive agents. Physicians who evaluate lung transplant patients for an acute abdomen should have a low threshold for surgical intervention.

Quality of life before and after lung transplantation in patients with emphysema versus other indications.

Whether lung transplantation improves Health-related Quality of Life in patients with emphysema and other end-stage lung diseases before and after lung transplantation was examined. Between 1992 and 1999, 23 patients with emphysema and 19 patients with other indications completed self-administered questionnaires before lung transplantation, and at 4, 7, 13, and 25 mo. after transplantation. The questionnaire included the Nottingham Health Profile, the State-Trait Anxiety Inventory, the Self-rating Depression Scale, the Index of Well-being, the self-report Karnofsky Index, and four respiratory-specific questions. Neither before nor after transplantation were significant differences found on most dimensions of Health-related Quality of Life between patients with emphysema and other indications. Before transplantation, both groups report major restrictions on the dimensions Energy and Mobility of the Nottingham Health Profile, low experienced well-being, depressive symptoms, and high dyspnea. About 4 mo. after transplantation, most Health-related Quality of Life measures improved significantly in both groups. These improvements were maintained in the following 21 mo.

Eosinophilic granulocytes and interleukin-6 level in bronchoalveolar lavage fluid are associated with the development of obliterative bronchiolitis after lung transplantation.

In a prospective cohort study, we assessed whether changes in total cell counts and differentiation and interleukin-6 (IL-6), IL-8, and monocyte chemoattractant protein-1 (MCP-1) concentrations in bronchoalveolar lavage fluid (BALF) are associated with a higher risk to develop obliterative bronchiolitis (OB). We investigated 60 lung transplant patients (follow-up of 2 to 8 yr) with either histologic evidence of OB within 1 yr after lung transplantation (n = 19) or no pathology, good outcome (GO) for at least 24 mo and well-preserved lung function, i.e., FEV > or = 80% of baseline (n = 41). Median time between lung transplantation and the first BAL was 42 d for the GO group and 41 d for the OB group (p > 0.05). In the bronchial fraction, median total cell counts (0.06 x 10(3)/ml versus 0.04 x 10(3)/ml), lymphocyte (9 x 10(3)/ml versus 2 x 10(3)/ml), and eosinophilic granulocyte counts (1 x 10(3)/ml versus 0) were significantly higher in the OB group than in the GO group (p < 0.05). In the alveolar fraction, this was the case for the median value of neutrophilic granulocyte counts (19 x 10(3)/ml versus 4 x 10(3)/ml), respectively. Median values of IL-6 and IL-8 concentrations in both bronchial (IL-6: 23 versus 6 pg/ml, IL-8: 744 versus 102 pg/ml) and alveolar fractions (IL-6: 13 versus 3 pg/ml, IL-8: 110 versus 30 pg/ml) of the BALF were significantly higher in the OB group than in the GO group. By means of logistic regression, we showed that higher total cell, neutrophilic granulocyte, and lymphocyte counts, the presence of eosinophilic granulocytes, and higher concentrations of IL-6 and IL-8 were significantly associated with an increased risk to develop OB. We conclude that monitoring cell counts, neutrophilic and eosinophilic granulocytes, IL-6, and IL-8 in BALF within 2 mo after lung transplantation in addition to the transbronchial lung biopsy (TBB) pathology will contribute to a better identification and management of the group of patients at risk for developing OB within a year.

Long-term renal outcome after lung transplantation is predicted by the 1-month postoperative renal function loss.

BACKGROUND: Progressive renal function loss is common after lung transplantation. To facilitate the design of renoprotective strategies, identification of early predictors for long-term renal function loss would be useful. METHODS: We prospectively analyzed renal function [glomerular filtration rate (GFR); 125I-iothalamate clearance] in a closely monitored cohort (minimum 24-month follow-up) of 57 patients who received lung transplants between November 1990 and September 1996 in our center. The analyzed end points were the slope of the GFR from 6 months posttransplant onward and the GFR at 24 months after transplantation. RESULTS: Before transplantation, the GFR was 100 ml/min (median, range 59-163). It decreased to 67 ml/min (29-123) at 6 months, 53 ml/min (17-116) at 24 months, and 51 ml/min (20-87) at 36 months after transplantation. The magnitude of the loss of GFR 1 month post-transplantation was the only factor significantly correlated with absolute GFR at 24 months after transplantation. Pulmonary diagnosis was significantly associated with long-term rate of renal function loss. Median loss of GFR was greatest in patients with cystic fibrosis (-10 ml/min/year, range -14 to -6 ml/min/year), preserved in pulmonary hypertension (-1 ml/min/year, range -6 to +7 ml/min/year), and in between in emphysema (-6 ml/min/year, range -27 to +12 ml/min/year). No other factors could be identified. CONCLUSIONS: In lung transplant recipients, the 1-month postoperative loss of GFR is an early marker for long-term renal prognosis. Pulmonary diagnosis appears to be a relevant predictor as well. These factors may guide further research and the development of preventive strategies.

Bronchiolitis obliterans syndrome after lung transplantation and health-related quality of life.

The present study was undertaken to assess the relationship between health-related quality of life (HRQOL) and bronchiolitis obliterans syndrome (BOS), as both represent important parameters of outcome after lung transplantation. HRQOL was measured both cross-sectionally and longitudinally by standardized patient self-administered questionnaires, including the Nottingham Health Profile, the State-trait Anxiety Inventory, the Zung Self-Rating Depression Scale, and the Index of Well-Being. Data were collected at 4 and 7 mo, and every 6 mo afterwards for as long as 49 mo post-transplantation. The number of patients who completed the questionnaires varied from 72 at 4 mo, to 27 at 49 mo after transplantation. Cross-sectionally, the patients with BOS reported persistently statistically significantly more restrictions on the dimensions energy and physical mobility of the Nottingham Health Profile compared with patients without BOS. Other domains, i.e., pain, sleep, social interaction, and emotional reactions, were not affected. Additionally, patients with BOS reported statistically significantly more depressive symptoms and anxiety 1 and 2 yr after transplantation. Results from the longitudinal analysis support these findings, although no change in depressive symptoms could be found after onset of BOS. This study suggests that all lung transplant recipients improve in HRQOL. The development of BOS, however, is associated with a significantly reduced HRQOL.

Decreased donor-specific cytotoxic T cell precursor frequencies one year after clinical lung transplantation do not reflect transplantation tolerance: a comparison of lung transplant recipients with or without bronchiolitis obliterans syndrome.

BACKGROUND: Decreased in vitro T cell alloreactivity, demonstrated by decreased frequencies of peripheral blood donor-specific T cell precursors, may reflect a tolerant state after transplantation and lower the risk for development of chronic graft dysfunction. It is unknown whether a decrease in donor-specific T cell frequencies also occurs after clinical lung transplantation and if such a decrease lowers the risk for bronchiolitis obliterans syndrome (BOS), a hallmark of chronic graft dysfunction. Therefore, we compared changes in posttransplant donor-specific cytotoxic T lymphocyte (CTLp) and helper T lymphocyte precursor (HTLp) frequencies in lung allograft recipients with good graft function and in recipients with BOS. METHODS: Donor and third party specific CTLp and HTLp frequencies were determined by limiting dilution assay in pre- and posttransplant (1 year) peripheral blood samples of lung allograft recipients with good graft function (n = 13) and BOS (n = 10). RESULTS: In recipients with good graft function, mean donor-specific CTLp frequencies decreased after transplantation (183 vs. 16 precursors before and after transplantation, respectively). Additionally, HTLp frequencies decreased but this was not specific for donor alloantigens because third party-specific HTLp frequencies decreased also. Surprisingly, recipients with BOS also showed a decrease in mean donor-specific CTLp frequencies after transplantation (332 vs. 49 precursors before and after transplantation, respectively). Again, HTLp frequencies decreased nonspecifically. CONCLUSIONS: We conclude that donor-specific CTLp frequencies decrease after lung transplantation, but that this does not result in transplantation tolerance protecting the lung against the development of chronic graft dysfunction.

Cartilaginous airway wall dimensions and airway resistance in cystic fibrosis lungs.

It is not clear how airway pathology relates to the severity of airflow obstruction and increased bronchial responsiveness in cystic fibrosis (CF) patients. The aim of this study was to measure the airway dimensions of CF patients and to estimate the importance of these dimensions to airway resistance using a computational model. Airway dimensions were measured in lungs obtained from CF patients who had undergone lung transplantation (n=12), lobectomy (n=1), or autopsy (n=4). These dimensions were compared to those of airways from lobectomy specimens from 72 patients with various degrees of chronic obstructive pulmonary disease (COPD). The airway dimensions of the CF and COPD patients were introduced into a computational model to study their effect on airway resistance. The inner wall and smooth muscle areas of peripheral CF airways were increased 3.3- and 4.3-fold respectively compared to those of COPD airways. The epithelium was 53% greater in height in peripheral CF airways. The sensitivity and maximal plateau resistance of the computed dose/response curves were substantially increased in the CF patients compared to COPD patients. The changes in airway dimensions of cystic fibrosis patients probably contribute to the severe airflow obstruction, and to increased bronchial responsiveness, in these patients.

Creatinine-based estimation of rate of long term renal function loss in lung transplant recipients. Which method is preferable?

BACKGROUND: Progressive renal function loss during long-term follow up is common after lung transplantation and close monitoring is warranted. Since changes in creatinine generation and excretion may occur after lung transplantation, the reliability of creatinine-based methods of renal function assessment to serial measurements of glomerular filtration rate (GFR) were compared in this population. METHODS: Renal function with serial measurements of GFR by iothalamate clearance every 6 months after transplantation was studied in a cohort of 40 lung transplant recipients with at least 24 months of follow up, transplanted between November 1990 and October 1995 in this center. The correlation between the rate of renal function loss calculated from the slope of GFR and the following creatinine-based indices: 1/S-creatinine, Cockcroft clearance and Levey estimation were analyzed. The absolute difference between GFR and Cockcroft clearance and Levey estimation pre- post-transplantation at several points was also studied. RESULTS: The slopes of 1/S-creatinine (r = 0.85), Cockcroft clearance (r = 0.86), and the Levey estimation (r = 0.84) correlated significantly with the slope of GFR as measured by iothalamate clearance. However, all creatinine-based slopes underestimate the rate of GFR loss. Cockcroft clearance and the reciprocal value of serum creatinine do not detect small GFR losses. During long-term follow up a time-dependent discrepancy between Cockcroft clearance, Levey estimation and GFR was observed which may partially explain the observations for this population. CONCLUSION: Creatinine-based slopes correlate with GFR slopes after lung transplantation, but consistently underestimate the rate of GFR decline. The Levey estimation is the most sensitive method used to detect small GFR losses and may be preferable when no GFR measurement is available. In special conditions when an accurate renal function assessment is needed true GFR may be necessary.

Visual symptoms after lung transplantation: a case of progressive multifocal leukoencephalopathy.

After solid organ transplantation, signs and symptoms of the central nervous system may present a diagnostic challenge. A 43-year-old patient developed a decrease in vision 15 months after bilateral lung transplantation. The initial diagnosis was a left posterior cataract, but left eye cataract extraction did not improve his vision. Seizures led to investigation of a broader differential diagnosis (cyclosporine intoxication, post-transplant lymphoproliferative disorder, infectious disease, chronic lymphatic leukemia). The clinical diagnosis of progressive multifocal leukoencephalopathy (PML) was confirmed by demonstration of JC virus in the cerebrospinal fluid and by autopsy findings. Modulation of the immunosuppressive regimen was unsuccessful. This case illustrates that decreased vision in immunocompromised patients may be the first manifestation of PML.

[Survival and impact of bronchiolitis obliterans syndrome after lung transplantation at the Academic Hospital Groningen, 1990/'98]. / Overleving en impact van bronchiolitis-obliteranssyndroom na longtransplantaties, verricht in het Academisch Ziekenhuis Groningen, 1990/'98.

OBJECTIVE: To describe the results of the lung transplantation programme in Groningen in relation to the bronchiolitis obliterans syndrome (BOS), in the first 118 consecutive patients. DESIGN: Retrospective. METHOD: Data were collected on the 118 patients subjected to lung transplantation in November 1990 to June 1998 in the University Hospital Groningen, the Netherlands, regarding the prevalence of chronic transplant dysfunction (BOS) and survival. RESULTS: 117 lung transplantations (95 bilateral lung transplantations including 2 retransplants, and 22 single lung transplantations) and 1 heart-lung transplantation had been performed. The patients were 70 males and 48 females with a mean age of 42 years (range: 9-64). The mean (SD) survival at 1, 2, 3 and 5 years post transplantation was 83% (3), 70% (4), 66% (5) and 61% (5) respectively. The median survival amounted to 2447 days. The mean (SD) prevalence of BOS at respectively 1, 2, 3 and 5 years post transplantation was 32% (5), 36% (5), 44% (5) en 54% (6). After a diagnosis of BOS stage I the median survival was 649 days. CONCLUSION: The survival of the lung transplant programme of the University Hospital Groningen is considered to compare favourably with other centres. The prevalence of BOS is considerable, and comparable with the prevalence of BOS reported by other programmes. BOS is associated with a decreased life expectancy.

Optimizing the balance between false positive and false negative error probabilities of confirmatory methods for the detection of veterinary drug residues.

GC-MS data on veterinary drug residues in bovine urine are used for controlling the illegal practice of fattening cattle. According to current detection criteria, peak patterns of preferably four ions should agree within 10 or 20% from a corresponding standard pattern. These criteria are rigid, rather arbitrary and do not match daily practice. A new model, based on multivariate modeling of log peak abundance ratios, provides a theoretical basis for the identification of analytes and optimizes the balance between the avoidance of false positives and false negatives. The performance of the model is demonstrated on data provided by five laboratories, each supplying GC-MS measurements on the detection of clenbuterol, dienestrol and 19 beta-nortestosterone in urine. The proposed model shows a better performance than confirmation by using the current criteria and provides a statistical basis for inspection criteria in terms of error probabilities.

The short and long term effects of intraoperative electron beam radiotherapy (IORT) on thoracic organs after pneumonectomy an experimental study in the canine model.

PURPOSE: The tolerance of mediastinal structures and thoracic organs to intraoperative radiotherapy (IORT) was investigated in the canine model. METHODS AND MATERIALS: Twenty-two adult beagles divided into three groups were subjected to a left pneumonectomy and IORT (10 MeV electrons) at doses of 20 Gy (n = 9), 25 Gy (n = 4), or 30 Gy (n = 9). Intraoperative electron beam radiotherapy was delivered through a 5 cm circular lucite cone encompassing a mediastinal field including the bronchial stump, aorta, esophagus, heart, phrenic nerve, contralateral hilar structures, and lung. Clinical monitoring was performed with regular chest X-ray, ECG, bronchoscopy, esofagoscopy, and fluoroscopy. From the different treatment dose groups, dogs were electively sacrificed at 1.5, 6, 12, and 72 months with complete autopsies. RESULTS: There was no bronchial stump dehiscence or acute morbidity. Four dogs developed radiation induced esophagitis (18%), one in the 20 Gy IORT group (11%) and three in the 30 Gy IORT group (33%). There were six IORT related mortalities (27.5%), one esophagoaortic fistula (4.5%) and five bronchovascular fistulas (23%): two in the 20 Gy IORT group (22%), two in the 25 Gy IORT group (50%) and two in the 30 Gy IORT group (22%). Histopathological findings in uncomplicated follow-up showed marked myointimal fibrosis in the muscular arteries, submucosal fibrosis of the esophagus, and interstitial fibrosis of bronchial and lung tissue, especially in the higher dose group. CONCLUSION: The mediastinal vascular, bronchial and esophageal structures are relatively sensitive to doses > 20Gy IORT. The IORT related morbidity found in this study may be lower when the current clinically used IORT doses of 10-15 Gy are applied. Further clinical application of IORT in the future treatment strategies for resectable nonsmall cell lung cancer may be worthwhile to investigate.

[Primary sarcoma of A. pulmonalis: a rare cause of cor pulmonale]. / Primair sarcoom van de A. pulmonalis: zeldzame oorzaak van cor pulmonale.

A 64-year-old female presented with fever and weight loss, accompanied by normochromic normocytic anaemia with high erythrocyte sedimentation rate. She developed severe cor pulmonale. Ventilation-perfusion scintigraphy revealed a non-matched perfusion defect of the entire right lung with impaired perfusion on the left side. The CT scan of the thorax revealed an intravascular mass which completely blocked the right pulmonary artery with incomplete obstruction of the pulmonary trunk. Treatment with anticoagulants was started but failed. The presumably thrombotic mass was removed by thoracotomy; the histopathological diagnosis was: sarcoma of the pulmonary artery, incompletely resected. Postoperatively, the condition of the patient showed initial improvement, but she later developed fatal mediastinitis. Pulmonary artery sarcoma is a rare cause of cor pulmonale. Diagnosis is usually only established at operation, curative resection is uncommon and the prognosis is therefore poor--most patients die within months after the diagnosis has been made.