Restrictive allograft syndrome post lung transplantation is characterized by pleuroparenchymal fibroelastosis.

We previously described restrictive allograft syndrome as a form of chronic lung allograft dysfunction, demonstrating restrictive pulmonary function decline. However, the histopathological correlates of restrictive allograft syndrome have yet to be satisfactorily described. We hypothesized that pulmonary pleuroparenchymal fibroelastosis, as has recently been described in bone marrow transplant recipients, may also be present in the lungs of patients with restrictive allograft syndrome. Retrospective review of 493 patients who underwent lung transplantation between 1 January 1996 and 30 June 2009, was conducted. Out of 47 patients with clinical features of restrictive allograft syndrome, 16 had wedge biopsy, re-transplant lung explant, or autopsy lung specimens available for review. All lungs showed varying degrees of pleural fibrosis. Fifteen of 16 showed parenchymal fibroelastosis, characterized by hypocellular collagen deposition with preservation and thickening of the underlying alveolar septal elastic network. The fibroelastosis was predominantly subpleural in distribution, with some cases also showing centrilobular and paraseptal distribution. A sharp demarcation was often seen between areas of fibroelastosis and unaffected lung parenchyma, with fibroblastic foci often present at this interface. Concurrent features of obliterative bronchiolitis were present in 14 cases. Another common finding was the presence of diffuse alveolar damage (13 cases), usually in specimens obtained <1 year after clinical onset of restrictive allograft syndrome. The single specimen in which fibroelastosis was not identified was obtained before the clinical onset of chronic lung allograft dysfunction, and showed features of diffuse alveolar damage. In conclusion, pleuroparenchymal fibroelastosis is a major histopathologic correlate of restrictive allograft syndrome, and was often found concurrently with diffuse alveolar damage. Our findings support a temporal sequence of diffuse alveolar damage followed by the development of pleuroparenchymal fibroelastosis in the histopathologic evolution of restrictive allograft syndrome.

Revisiting the pathologic finding of diffuse alveolar damage after lung transplantation.

BACKGROUND: Diffuse alveolar damage (DAD) is a non-specific pathologic diagnosis frequently encountered after lung transplantation. We examined the relationship between DAD and different forms of chronic lung allograft dysfunction (CLAD). METHODS: We reviewed the results of 4,085 transbronchial biopsies obtained from 720 lung transplant recipients. DAD detected in biopsies within 3 months and newly detected DAD after 3 months were defined as early DAD and late new-onset DAD, respectively. Among patients with CLAD (FEV(1) <80% baseline), restrictive allograft syndrome (RAS) was defined by a decline in total lung capacity to <90% baseline and bronchiolitis obliterans syndrome (BOS) as CLAD without restrictive allograft syndrome (RAS). Kaplan-Meier analyses and multivariate proportional hazard models were used. RESULTS: DAD was observed in 320 of 720 (44.4%) patients at least once; early and late new-onset DAD were observed in 264 of 707 (37.3%) and 87 of 655 (13.3%) patients, respectively. Early DAD was associated with significantly higher 90-day mortality (20 of 264 [7.6%] vs 11 of 443 [2.5%]; p = 0.001). Moreover, among 502 bilateral lung transplant recipients who had sufficient pulmonary function tests to distinguish BOS and RAS, early DAD was associated with earlier BOS onset (hazard ratio [HR] 1.24; confidence interval [CI] 1.04 to 1.47; p = 0.017; median time of BOS onset: 2,902 vs 4,005 days). Conversely, treated as a time-varying covariate, late new-onset DAD was a significant risk factor for RAS in a Cox model (HR 36.8; CI 18.3 to 74.1; p < 0.0001). CONCLUSIONS: Early DAD is associated with early mortality and BOS, and late new-onset DAD increases the risk of RAS.

Restrictive allograft syndrome (RAS): a novel form of chronic lung allograft dysfunction.

BACKGROUND: Bronchiolitis obliterans syndrome (BOS) with small-airway pathology and obstructive pulmonary physiology may not be the only form of chronic lung allograft dysfunction (CLAD) after lung transplantation. Characteristics of a form of CLAD consisting of restrictive functional changes involving peripheral lung pathology were investigated. METHODS: Patients who received bilateral lung transplantation from 1996 to 2009 were retrospectively analyzed. Baseline pulmonary function was taken as the time of peak forced expiratory volume in 1 second (FEV(1)). CLAD was defined as irreversible decline in FEV(1) < 80% baseline. The most accurate threshold to predict irreversible decline in total lung capacity and thus restrictive functional change was at 90% baseline. Restrictive allograft syndrome (RAS) was defined as CLAD meeting this threshold. BOS was defined as CLAD without RAS. To estimate the effect on survival, Cox proportional hazards models and Kaplan-Meier analyses were used. RESULTS: Among 468 patients, CLAD developed in 156; of those, 47 (30%) showed the RAS phenotype. Compared with the 109 BOS patients, RAS patients showed significant computed tomography findings of interstitial lung disease (p < 0.0001). Prevalence of RAS was approximately 25% to 35% of all CLAD over time. Patient survival of RAS was significantly worse than BOS after CLAD onset (median survival, 541 vs 1,421 days; p = 0.0003). The RAS phenotype was the most significant risk factor of death among other variables after CLAD onset (hazard ratio, 1.60; confidential interval, 1.23-2.07). CONCLUSIONS: RAS is a novel form of CLAD that exhibits characteristics of peripheral lung fibrosis and significantly affects survival of lung transplant patients.

Survival of lung transplant patients with cystic fibrosis harboring panresistant bacteria other than Burkholderia cepacia, compared with patients harboring sensitive bacteria.

BACKGROUND: The impact of panresistant bacteria, other than Burkholderia cepacia, on the survival after lung transplantation in patients with cystic fibrosis (CF) remains controversial. METHODS: To determine the impact of panresistant bacteria in CF patients on survival after lung transplantation a retrospective multicenter study was performed. All lung transplant recipients with a pre-transplant diagnosis of CF, at the University of Toronto (n = 53) and Duke University (n = 50), were included. Patients were included in the panresistant group if at least one specimen isolated from their respiratory secretions grew bacteria resistant or intermediate to all classes of antibiotics tested. Patients with sensitive or resistant B cepacia were excluded because of its adverse impact upon post-transplant survival. RESULTS: Forty-five of 103 (43.7%) patients harbored panresistant bacteria (43 had Pseudomonas aeruginosa, 1 had Stenotrophomonas maltophilia, and 1 had Achromobacter xylosoxidans). According to log-rank test, there was decreased survival in patients with panresistant bacteria compared to patients with sensitive bacteria (survival: 91.1 +/- 4.2% vs 98.3 +/- 1.7% at 3 months; 88.6 +/- 4.8% vs 96.6 +/- 2.4% at 1 year; 63.2 +/- 8.6% vs 90.7 +/- 4.0% at 3 years; 58.3 +/- 9.2% vs 85.6 +/- 5.2% at 5 years; p = 0.016). The results did not differ significantly between the two centers. Both groups had similar or better survival than CF patients as reported by the United Network of Organ Sharing (UNOS) registry (1-year, 86.0%; 3 years, 65.4%; 5 years, 49.6%). CONCLUSIONS: Patients with CF harboring panresistant bacteria have slightly decreased survival, but their survival is comparable to the results published by the UNOS registry.

Incidence and prevalence of diabetes mellitus in patients with cystic fibrosis undergoing lung transplantation before and after lung transplantation.

Cystic fibrosis (CF) related diabetes mellitus (DM) occurs in 15% of adult pancreatic insufficient CF patients. Lung transplantation is a treatment option for end-stage CF. We hypothesized that the prevalence of DM increases after lung transplantation. The study population included adult patients undergoing lung transplantation from March 1988 to March 2002 for end-stage CF at the University of Toronto. Demographic data, exocrine pancreatic function, presence of DM before and after transplant, as well as timing of its development after transplant were collected. Eighty-six patients met the study criteria; 77 of 86 (89.5%) of patients were pancreatic insufficient and were further analyzed. Median follow-up post-transplant was 3.3 yr (interquartile range: 1.2-7.2). Their mean age was 29.7 +/- 8.1 yr and 46 of 77 (59.7%) were male. The prevalence of DM increased from 22 of 77 (28.6%) before transplant to 38 of 77 (49.4%) after transplant (p = 0.008). The median time of DM development after transplant was 80 d (range: 13-4352). Sixteen of 55 (29.1%) of pancreatic insufficient patients who were non-diabetic prior to transplant, developed DM after transplant. DM is common in CF patients undergoing lung transplantation and the prevalence increases after transplant.

Upper lobe fibrosis: a novel manifestation of chronic allograft dysfunction in lung transplantation.

BACKGROUND: Lung transplantation is an established treatment modality for a number of chronic lung diseases. Long-term survival after lung transplantation is limited by chronic allograft dysfunction, usually manifested by bronchiolitis obliterans syndrome. We describe a case series with upper lobe fibrosis, a novel presentation of chronic allograft dysfunction. METHODS: We reviewed lung transplants at the Toronto General Hospital and Duke University Hospital from 1990 to 2002 and identified patients with upper lobe fibrosis. RESULTS: Thirteen of 686 patients (6 women) developed upper lobe fibrosis (Toronto, 9; Duke, 4); 12 of 13 had bilateral transplants. The median age at diagnosis was 42 years (range, 19-70). Primary diagnoses were cystic fibrosis, 6; emphysema, 4; sarcoidosis, 1; and pulmonary fibrosis, 2 patients. Radiographic diagnosis was made at a median of 700 days post-transplant (range, 150-2,920). Pulmonary function tests demonstrated predominantly a progressively worsening restrictive pattern. Open lung biopsy specimens revealed dense interstitial fibrosis, with occasional features of obliterative bronchitis, bronchiolitis obliterans obstructive pneumonia, and aspiration. Nine patients died at a median follow-up of 2,310 days (range, 266-3,740), 8 due to respiratory failure. CONCLUSION: Upper lobe fibrosis is a novel presentation of chronic allograft dysfunction in lung transplant recipients and is differentiated from bronchiolitis obliterans syndrome on the basis of physiologic and radiologic findings.

Pre-transplant panel reactive antibody in lung transplant recipients is associated with significantly worse post-transplant survival in a multicenter study.

BACKGROUND: The presence of antibodies to human leukocyte antigens (HLA) prior to transplantation has been linked to worse post-transplant outcomes in many solid organ transplants. The effect of these antibodies is less clear in lung transplant recipients, although previous studies have suggested an increased incidence of allograft dysfunction. METHODS: A retrospective study of all first lung transplant recipients from the University of Toronto (November 1983-July 2001, n = 380) and Duke University (April 1992-June 2000, n = 276) was performed. Demographic data, survival information, and level of last pre-transplant panel reactive antibody (PRA) were collected. PRA level was measured by the complement-dependent cell cytotoxicity assay at both centers. Survival analysis was performed using the Kaplan-Meier method, and groups were compared with the Wilcoxon rank sum test. RESULTS: Of 656 lung transplant recipients, 101 (15.4%) had a PRA greater than 0, 37 (5.6%) had a PRA greater than 10%, and 20 (3.0%) had a PRA greater than 25%. Patients with a PRA greater than 25% had decreased median survival than did the rest of the patients (1.5 vs 5.2 years) and at 1 month (70% vs 90%), 1 year (65% vs 76%), and 5 years (31% vs 50%), respectively (p = 0.006, Wilcoxon's rank sum test) test). CONCLUSION: Significant elevation of PRA prior to lung transplantation is associated with worse survival, especially in the early post-transplant period. This may be due to a direct effect of anti-HLA antibodies on the allograft. The effectiveness of treatments such as plasmapheresis and intravenous immunoglobulin prior to transplantation needs to be evaluated.

Bile acid aspiration and the development of bronchiolitis obliterans after lung transplantation.

BACKGROUND: Aspiration of gastroesophageal refluxate may contribute to lung transplant bronchiolitis obliterans syndrome (BOS). We investigated bile acids in bronchoalveolar lavage fluid (BALF) and studied its role in BOS. MATERIALS AND METHODS: Surveillance pulmonary function tests and BALF were evaluated in 120 lung recipients. BOS-(0p-3) was diagnosed after 6 months' survival. BOS was defined as "early" if diagnosed within 12 months after a transplant. BALF was assayed for differential cell count, bile acids, and interleukins 8 and 15. Bile acids were considered elevated if greater than normal serum levels ( or =8 micromol/L). RESULTS: Elevated BALF bile acids were measured in 20 (17%) of 120 patients. BOS was diagnosed in 36 (34%) of 107 patients and judged "early" in 21 (57%) of 36. Median BALF bile acid values were 1.6 micromol/L (range, 0-32 micromol/L) in BOS patients and 0.3 micromol/L (range, 0-16 micromol/L) in non-BOS patients ( P = .002); 2.6 micromol/L (range, 0-32 micromol/L) in early BOS patients and 0.8 micromol/L (range, 0-4.6 micromol/L) in late BOS patients, ( P = .02). Bile acids correlated with BALF IL-8 and alveolar neutrophilia (r = 0.3, P = .0004, and r = 0.3, P = .004, respectively), but not with IL-15. Freedom from BOS was significantly shortened in patients with elevated BALF bile acids (Cox-Mantel test, P = .0001). CONCLUSIONS: Aspiration of duodenogastroesophageal refluxate is prevalent after lung transplantation and is associated with the development of BOS. Elevated BALF bile acids may promote early BOS development via an inflammatory process, possibly mediated by IL-8 and alveolar neutrophilia.

Bronchiolitis obliterans syndrome in lung transplant recipients: can thin-section CT findings predict disease before its clinical appearance?

PURPOSE: To determine whether there are thin-section computed tomographic (CT) features that predict bronchiolitis obliterans syndrome (BOS) in lung transplant recipients before the clinical appearance and during the early stages of the disease. MATERIALS AND METHODS: Two hundred ninety-eight thin-section CT scans obtained in 26 lung transplant recipients who did (study group) and 26 lung transplant recipients who did not (control group) develop BOS were reviewed for the presence of mosaic perfusion, bronchiectasis, bronchial wall thickening, and air trapping. BOS was defined by using the recently revised definition of the International Society for Heart and Lung Transplantation. CT scans obtained in the BOS group were divided into three groups: Group A consisted of the last scans obtained before the clinical appearance of BOS; groups B and C consisted of, respectively, the first and last scans obtained after the clinical appearance of BOS. Scans obtained in the control group were acquired during similar posttransplantation periods and matched to scans in each BOS group. Sensitivity, specificity, and positive and negative predictive values were calculated separately for each subgroup. The optimal threshold for each thin-section CT-depicted abnormality was defined by using receiver operating characteristics analysis. RESULTS: The sensitivities of air trapping for the diagnosis of BOS during the periods in which the scans in groups A, B, and C were obtained were 50%, 44%, and 64%, respectively; specificities were 80%, 100%, and 80% respectively. Sensitivities of mosaic perfusion were 4%, 20%, and 36%, respectively; specificities were 100%, 96%, and 96%, respectively. Sensitivities of bronchiectasis were 25%, 24%, and 32%, respectively; specificities were 80%, 80%, and 96%, respectively. Sensitivities of bronchial wall thickening were 4%, 24%, and 40%, respectively; specificities were 96%, 84%, and 80%, respectively. Air trapping was seen intermittently in nine (43%) of 21 patients with CT scans that depicted this finding at least once. CONCLUSION: The value of the finding of air trapping before the clinical appearance and during the early stages of BOS is lower than has been previously reported. When using the recently revised criteria for BOS, the role of thin-section CT as a screening test to evaluate patients with lung transplants appears to be limited.

Risk quantification of early outcome after lung transplantation: donor, recipient, operative, and post-transplant parameters.

BACKGROUND: Because there is no reliable evaluation system of recipient acuity after lung transplantation, comparing patients among centers is difficult. The purpose of our study was to identify risk factors for 30-day mortality and prolonged intensive care unit stay and to develop a scoring system to evaluate the severity of impairment and to predict surgical outcomes. METHODS: We prospectively collected data from 122 lung transplant recipients and from 119 donors from January 1997 to June 2000. We assessed donor, recipient, and operative factors; ischemic time; and immediate post-operative physiologic parameters to identify risk factors for 30-day mortality and prolonged intensive care unit stay. Furthermore, we sub-classified these factors into grades to develop a scoring system for predicting surgical outcomes. RESULTS: Cardiopulmonary bypass use, body mass index >25 kg/m2, immediate post-operative systolic pulmonary arterial pressure, trend of oxygenation index from 12 to 24 hours after transplantation, and the Acute Physiology and Chronic Health Evaluation II score correlated significantly with outcomes, and the sum of these 5 scores correlated strongly with outcomes (p < 0.0001). CONCLUSIONS: We conclude that the total score of these 5 risk factors could be used to predict 30-day mortality and prolonged intensive care unit stay. This scoring system also will facilitate standardization among transplant centers in evaluating post-transplant severity of illness.

Fibrosis of the upper lobes: a newly identified late-onset complication after lung transplantation?

OBJECTIVE: The objective of this study was to describe the high-resolution CT findings of a previously unreported rare complication observed in seven patients who had undergone lung transplantation. CONCLUSION: High-resolution CT findings suggestive of gradual progressive lung fibrosis, predominantly in the upper lobes with relative sparing of the basal segments, may represent a specific and rare type of rejection of still unknown cause in lung transplant recipients.

Marginal donor lungs: a reassessment.

OBJECTIVE: Lung transplantation is limited by the shortage of suitable donors. To overcome this problem, many programs have begun to use marginal or extended donors after reports suggesting equivalent outcomes with no additional risk. As our use of extended donor lungs increased and our recipient selection criteria expanded, we believed it was appropriate to reevaluate outcomes with extended donor lungs compared with outcomes with standard donor lungs and recipients outside of the currently accepted guidelines. METHODS: We performed a retrospective review of 128 consecutive lung or heart-lung transplants from January 1, 1997, to June 30, 2000. The primary endpoint was 30-day mortality. Donors were considered extended if any one of the following criteria were met: age greater than 55 years, smoking longer than 20 pack-years, presence of chest radiographic film infiltrate, PO (2) of less than 300 mm Hg, or purulent secretions on bronchoscopy. Guideline and nonguideline recipients were defined on the basis of previously published criteria. RESULTS: Of a total of 123 donors, 63 (51%) were extended. Forty-eight donors failed 1 criterion, 10 failed 2 criteria, and 5 failed 3 criteria. One hundred twenty-eight transplants were performed. The 30-day mortality for the standard donor group was 4 (6.2%) of 65 versus 11 (17.5%) of 63 for the extended donor group (P =.047). CONCLUSIONS: Although many extended donor lungs will result in acceptable postoperative function, caution needs to be exercised in the uses of certain extended donor lungs because there seems to be an increased early mortality rate in that group of recipients. Nonguideline recipients appear to have acceptable early mortality, except when they received extended donor lungs.

Inspiratory and expiratory helical CT of normal adults: comparison of thin section scans and minimum intensity projection images.

SUMMARY: To evaluate and compare thin section CT scans (TSS) and minimum intensity projection images (MinIPs) in healthy individuals, 10 nonsmokers with normal pulmonary function tests were studied using ten 1-mm collimated, helically acquired TSS images after full inspiration and expiration at two anatomic levels. Ten-millimeter-thick MinIPs were generated from the helical scans. Two thoracic radiologists compared TSS and MinIPs for artifacts and air trapping. Hounsfield unit (HU) measurements of TSS and MinIPs were obtained. The lung parenchyma on MinIPs demonstrates a smooth anterior-to-posterior attenuation gradient, accentuated by expiration. Motion and beam-hardening artifacts on TSS images resulted in regions of high and low attenuation on MinIPs, respectively. Expiratory TSS and MinIPs demonstrated air trapping (n = 31/40; range, 0-25%; mean, 7.2%). In comparison with TSS, MinIPs improved the conspicuity of air trapping (n = 20) and appeared to detect more air trapping (n = 7). No statistical differences were found when comparing the mean HU values of TSS and MinIPs. MinIPs demonstrated a smooth anterior-to-posterior attenuation gradient. Compared with TSS, MinIPs improve the conspicuity of air trapping in healthy individuals. Therefore, expiratory MinIPs may be useful in detecting air trapping as a result of disease.