Search

Context: The medical record is frequently used in clinical studies as a source of information on illness events experienced by patients; however, it may be incomplete., Objective: To estimate the extent of incompletely documented acute bronchopulmonary events in a transplant clinic medical record at a single university medical center, using home monitoring data., Design, Setting, and Subjects: Trends in daily home monitoring data were compared to contemporaneous medical record documentation at 150 different times in 30 lung transplant recipients over 45 subject-years., Outcome Measure: Proportion of acute bronchopulmonary illness events documented in clinic medical record., Results: By using home monitoring data in a new way, we found that 40% of events actually suffered by lung recipients could not be ascertained to have occurred from the clinic medical record alone. All missed encounters occurred away from the transplant clinic, and involved hospitalizations and telephone prescriptions., Conclusions: Using the clinic medical record alone to identify acute bronchopulmonary events in lung transplant recipients may result in missing 40% of events. This has important ramifications for studies relying on the medical record for acute event ascertainment in lung transplantation and possibly other chronic diseases.

Purpose The objective of this study was to develop and evaluate a computerized rule-based decision support algorithm for nursing triage of potential acute bronchopulmonary events in lung transplant recipients on the basis of home monitoring of spirometry and symptoms. Methods The algorithm automatically separates recipients into 2 groups: those who are stable or improving and those who should be "watched" further because of their potential for developing bronchopulmonary events according to their weekly home-monitoring measurements. A total of 155 recipients (82 females and 73 males) contributed 1944 weekly records for the training (420), testing (786), and prospective evaluation (738) data sets. Weekly records contained daily values of forced expiratory volume at 1 second and respiratory symptoms, which were the inputs for the triage rules. Results Sensitivity and specificity were greater than 90% for the prospective evaluation comparing the computer decision support system with the manual nurse review of the same home-monitoring reports. Conclusions Algorithm performance in identifying lung recipients who should be placed on a "watch" list for the potential to develop acute bronchopulmonary events is comparable to the standard human clinical review of the same weekly home-monitoring data.

Chronic allograft rejection remains a leading cause of morbidity and mortality in lung transplant recipients. Currently, diagnosis is based on lung biopsies or the presence of bronchiolitis obliterans syndrome (BOS). To identify a biomarker of rejection we performed a proteome survey of archived bronchoalveolar lavage fluid (BALF) acquired from lung transplant recipients between 1993 and 1996 using mass spectrometry (MS). A total of 126 BALF samples from 57 individuals were tested. Initial MS assessment revealed numerous differences in a majority of individuals who experienced BOS, but three unusually intense peaks at m/z = 3373, 3444, and 3488. These were identified as human neutrophil peptides 1-3 (HNP). Quantification by enzyme-linked immunoabsorbent assay showed an elevated HNP level (>0.3 ng/microg protein) in 89% of patients who developed BOS2-3 within 15 months, reaching as high as 6% of the total BALF protein. In control patients, 35% demonstrated a slightly elevated HNP level that declined in all who had subsequent BALF available for testing. HNP levels did not correlate with episodes of acute rejection, cytomegalovirus or fungal infection. In conclusion, elevated HNP levels are associated with the onset of BOS and can predate the clinical onset of disease up to 15 months.

Background: Extracorporeal membrane oxygenation (ECMO) has been used successfully for early, severe reperfusion injury after lung transplantation. The purposes of this study are to: (1) document the medium-term survival of patients treated with ECMO; and (2) assess the extent of recovery of their pulmonary function., Methods: We retrospectively reviewed charts of 172 patients having lung transplants at our institution from 1997 through 2002. The group included 16 patients (9% of total; 10 bilateral, 5 single, 1 living lobar) treated with ECMO for primary allograft failure after single or bilateral single-lung transplantation. Survival and bronchiolitis obliterans syndrome (BOS)-free survival rates were calculated. Pulmonary function was assessed at 2 months, 1 year and 2 years post-transplant., Results: Median hospital stay was 48 days for the ECMO group and 16 days for the overall group (p < 0.05). The 90-day survival was 60% in the ECMO group, and 90% in the overall group. The 2-year survival was 46% in the ECMO group, and 69% in the overall group. Mean forced expiratory volume in 1 second (FEV(1)) in the ECMO group at 1 year was 59 +/- 13% of predicted, and at 2 years 60 +/- 15% of predicted; it was not significantly different for the overall group., Conclusions: Patients treated with ECMO for primary allograft failure after lung transplantation showed acceptable medium-term survival and pulmonary function.

Ag recognition by OVA-reactive OT-II (I-Ab restricted) and DO11.10 (I-Ad restricted) TCR-Tg CD4+ T cells after heterotopic transplantation of OVA transgene-expressing tracheal grafts was examined as a model of minor histocompatibility Ag (mHAg)-induced chronic allograft rejection. In response to airway allotransplantation with grafts expressing the OVA transgene, these TCR-Tg CD4+ T cells expressed the activation markers CD69 and CD44, demonstrated evidence of blastogenesis, underwent multiple rounds of cell division leading to their clonal expansion in the draining lymph node, and proceeded to differentiate to a effector/memory T cell phenotype based on a reduction in the expression of CD45RB. These mHAg-specific TCR-Tg CD4+ T cells responded equally well to fully MHC-mismatched tracheas and to class II-deficient allografts, demonstrating that donor mHAg recognition by recipient CD4+ T cells does not rely on Ag presentation by donor-derived APC. The activation of mHAg-specific TCR-Tg CD4+ T cells after their adoptive transfer into recipient mice given MHC-matched, but mHAg-disparate, airway allografts was associated with their movement into the allograft and the near uniform destruction of the transplanted airway tissue secondary to the development of obliterative airways disease. These results demonstrate that an activation of mHAg-reactive CD4+ T cells in the draining lymph node by recipient APC that indirectly express graft mHAg-derived peptide/class II MHC complexes precedes responder T cell proliferation and differentiation, and leads to the eventual migration of these alloreactive T cells to the transplanted airway tissue and the promotion of chronic graft rejection.

Human T cells responding against transplanted allogeneic lung tissue have been implicated in late graft failure secondary to obliterative bronchiolitis. This obliterative airways disease (OAD) also develops in heterotopic murine tracheal allografts in association with graft infiltration by both CD8(+) and CD4(+) T cells. To date, there has been little evidence to suggest that directly alloreactive CD8(+) T cells either promote chronic rejection or lead to the development of OAD following airway allotransplantation. Using L(d)-specific TCR-Tg 2C CD8(+) T cells adoptively transferred into wild-type B6 (H-2(b)) mice and the transplantation of BALB/c (H-2(d)) tracheal allografts, we now show that the direct recognition of donor-specific class I MHC molecules by host CD8(+) T cells leads to their activation, clonal expansion within the graft, and differentiation to an effector phenotype with the capacity to induce airway fibrosis. In addition, these experiments demonstrate that ongoing direct alloantigen recognition within the transplanted airway tissue is necessary for the recruitment and retention of these directly alloreactive CD8(+) T cells. Thus, these experiments are the first to definitively show a role for directly alloreactive CD8(+) T cells in the chronic rejection that leads to OAD.

Lung transplantation is effective for many diseases that are unresponsive to other therapy. However, long-term survival of recipients is limited by the development of bronchiolitis obliterans syndrome. Acute rejection is a major risk factor for bronchiolitis obliterans syndrome, but noninvasive biomarkers have not been identified. To address this deficiency, gene expression microarrays were performed using bronchoalveolar lavage cells of lung transplant recipients with acute rejection (n = 7) and with no rejection (n = 27). The cell and differential counts were similar. Signal values for genes between groups were compared using t tests. One hundred thirty-five genes were upregulated in the acute-rejection group, including genes involved in acute rejection, immune response genes with an unknown role in rejection, genes not known to have a role in rejection, and genes of unknown function. Two-dimensional hierarchical clustering grouped all acute rejection samples into one cluster and the majority of the no-rejection samples into a second cluster. The acute-rejection samples showed significant changes in gene expression for seven biological pathways. Bronchoalveolar lavage cells are a reliable RNA source for microarray analysis, which is powerful in identifying acute-rejection genes. The individual genes, patterns of gene expression, or biologic pathways identified may represent novel biomarkers for acute rejection.

Home monitoring by lung transplant recipients has been effective for early detection of clinical problems. This study used an electronic diary for home monitoring by lung transplant candidates to improve communication between candidates and the transplant team. Candidates were randomized into control (52 subjects following standard telephone reporting procedures) and intervention (67 subjects using an electronic diary to record and transmit a range of health-related measures) groups. Outcome measures were monitoring adherence and level of communication (for monitor acceptability and utilization), hospital length of stay after transplantation and survival at 4 months (for clinical effectiveness). Subjects used the diary without difficulty and with good adherence. Subjects and coordinator contacts were similar between groups; intervention group subjects were positive regarding contact based on diary use. There were no significant differences in clinical outcomes between groups. Changing diary questions might improve the effectiveness of electronic monitoring for lung transplant candidates.

Over the last 2 decades, mechanical circulatory support devices have been developed with the goal of supporting patients with advanced heart failure as a bridge to cardiac transplantation, a bridge to recovery, and an alternative to transplantation (also called chronic or destination therapy). The current generation of devices provides a differentiated spectrum of circulatory support. The major limitations of mechanical circulatory support devices are infection, coagulopathies and device dysfunction. The Scientific Council on Mechanical Circulatory Support of the International Society for Heart and Lung Transplantation has established an international database to generate critical data to advance knowledge about the effectiveness of mechanical circulatory support device therapy for one of the most difficult and costly contemporary medical problems, the malignant syndrome of advanced heart failure.

Goal: The goal of this study was to assess the efficacy of sirolimus in lung-transplant recipients., Methods: The study was designed as a single center, consecutive case study of lung-transplant recipients treated with sirolimus, tacrolimus, and prednisone. All study subjects also received an HMG-CoA reductase inhibitor, and prophylaxis for cytomegalovirus and Pneumocystis carinii., Results: A total of 15 subjects were enrolled in the study. Within 6 months, significant airway complications occurred in four subjects, three of whom died. At that point, the investigators terminated enrollment in the study. The study population was compared retrospectively with a group of 83 consecutive lung recipients treated with cyclosporine (n=64) or tacrolimus (n=19), mycophenolate mofetil, and prednisone. This confirmed an increased incidence of airway dehiscence and reduced survival in the sirolimus-treated patients. Sirolimus-treated patients had a low incidence of acute rejection. No significant differences were noted in the incidence of bacterial or fungal bronchopulmonary infections., Conclusions: We observed an unexpectedly high incidence of postoperative airway dehiscence in lung-transplant recipients treated with sirolimus, in combination with tacrolimus, prednisone, and an HMG-CoA inhibitor. Further studies will be needed to determine the safety and efficacy of using sirolimus after complete airway healing has occurred.

Background: Chronic allograft rejection manifested as bronchiolitis obliterans syndrome (BOS) is the leading cause of late death after lung transplantation. Although increasing evidence suggests an association between anti-human leukocyte antigens (HLA) antibodies and chronic rejection of kidney or heart allografts, the clinical significance of anti-HLA antibodies in lung recipients is less clear, especially in previously unsensitized recipients. The use of flow cytometry based panel reactive antibody (flow-PRA) provides a highly sensitive means to identify the development of de novo anti-HLA antibodies in lung recipients., Methods: Flow-PRA testing was used to analyze the pre- and posttransplant sera in stable BOS free lung recipients who survived at least 6 months. Patients without prior sensitization as defined by a negative pretransplant flow-PRA were analyzed posttransplant for the presence of anti-HLA antibodies by flow-PRA. A proportional hazards model was used to determine the impact of anti-HLA antibody on BOS risk., Results: Sera from 90 recipients at Duke University with negative pretransplant flow-PRA were tested by flow-PRA at various time points after transplant. Sera from 11% (10/90) of recipients were found to contain anti-HLA antibodies detectable by flow-PRA. Nine patients (90%) developed anti-HLA antibodies specific for donor antigens, and one patient developed anti-HLA class II antibodies, not specific to donor antigens. Among the nine patients with donor antigen specific antibodies, flow-PRA specificity analysis demonstrated eight were specific for class II antigens and one for class I antigens. In a multivariate model that controls for other BOS risk factors, a positive posttransplant flow-PRA was significantly associated with BOS grades 1,2, or 3 (hazard ratios [HR] 3.19; 95% confidence interval [CI]: 1.41-7.12, P=0.005) and BOS grade 2 or 3 (HR 4.08; 95% CI: 1.66-10.04, P=0.002). Four patients with de novo anti-HLA antibodies died during follow-up; all four had BOS. Among BOS patients, the presence of anti-HLA antibodies was associated with a significantly worse survival (P =0.05, log-rank test)., Conclusions: Although uncommon, previously unsensitized lung transplant recipients can develop anti-HLA antibodies to donor class II antigens. The development of de novo anti-HLA antibodies significantly increases the risk for BOS, independent of other posttransplant events. Furthermore, de novo anti-HLA antibodies identify BOS patients with significantly worse survival. Additional studies are needed to determine if class II-directed anti-HLA antibodies contribute mechanistically to the chronic rejection process in lung recipients.

Background: Up to 50% of human lung allografts develop chronic rejection manifested as obliterative bronchiolitis (OB). This complication frequently progresses despite maximal immunosuppression, suggesting that, once initiated, factors other than alloimmunity play a role in its progression. In animals, heterotopically transplanted allograft airways develop obliterative airway disease (OAD), an immunologically mediated lesion that is used as a preclinical model of OB. We sought to determine whether OAD would progress even after removal from the alloimmune environment., Methods: Tracheas from Lewis rats were transplanted subcutaneously into Brown Norway recipients to create allografts. After 7 or 14 days of alloimmune stimulus, these allografts were removed and retransplanted into an isogeneic environment for an additional 21 days. Histology was assessed at each time point, with quantitation of the airway epithelium and intraluminal fibroproliferation., Results: Allografts exposed to 14 days of alloimmune stimulus had a significant loss of airway epithelium compared with grafts exposed to only 7 days ( <0.001). There was little fibroproliferation seen in either of these groups. After retransplantation, the grafts initially exposed to 7 days of alloimmune stimulus had few abnormalities. In contrast, the group exposed initially to 14 days of alloimmunity and retransplanted had near complete obliteration of the lumen with fibroproliferation (96.9% occlusion, =0.001) and absent airway epithelium., Conclusions: OAD progresses despite removal of alloimmunity if the initial period of alloimmune injury is sufficient. Airway epithelial loss correlated with progression to fibroproliferation, suggesting that the epithelium plays a significant role in the pathogenesis of OB.

Background: Renal failure is a common complication following non-renal solid organ transplantation. The purpose of our study was to define the rate of decline in renal function and to identify independent risk factors associated with renal failure following lung or heart-lung transplantation., Methods: Between May 1986 and December 1998, 219 patients underwent lung or heart-lung transplantation at the University of Minnesota and survived at least six months (33 heart-lung, 66 bilateral single lung, and 120 unilateral single lung transplants). The mean age at the time of transplant was 45.9 +/- 11.6 years (mean +/- SD; range, 15 to 65 years), and the mean pre-transplant serum creatinine level was 0.88 +/- 0.19 mg/dL. All patients were treated with a calcineurin inhibitor (164 cyclosporine, 55 tacrolimus)., Results: During the follow-up period (median 44 months, range 6.8 to 163 months), 16 patients (7.3%) developed end-stage renal disease. The cumulative incidence of doubling of serum creatinine was 34% at one year, 43% at two years and 53% by five years. Factors associated with the primary end point of the time to doubling of the baseline serum creatinine by proportional hazards regression were cumulative periods with diastolic blood pressure greater than 90 mm Hg [relative risk (RR) 1.30, P = 0.02] and the serum creatinine value at one month post-transplantation (RR 1.28, P = 0.03). Use of tacrolimus during the first six months after transplantation was associated with a significant decrease in the risk for time to doubling of serum creatinine (RR 0.38, P = 0.009) and a lower rate of acute rejection., Conclusions: These results suggest that potential renoprotective strategies following lung or heart-lung transplantation include avoidance of peri-transplant renal injury, diligent blood pressure control, and preferential use of tacrolimus over cyclosporine.

Unlabelled: BACKGROUND; Chronic rejection manifested as obliterative bronchiolitis (OB) and bronchiolitis obliterans syndrome (BOS) continue to be major causes of morbidity and mortality after lung transplantation. Community respiratory virus (CRV) infection, including respiratory syncytial virus, parainfluenza virus, and influenza virus, can infect and also cause morbidity in lung transplant recipients. Because CRV and OB/BOS affect the small airways, we sought to determine whether CRV infections predisposed patients to OB/BOS., Methods: To determine whether CRV predisposed to OB/BOS, a proportional hazards regression analysis of time to OB/BOS was performed with CRV as a time-dependent covariate. To determine the influence of OB/BOS on the subsequent development of CRV infection, we reversed the outcome and time-dependent covariate. To illustrate the effect of CRV on OB/BOS and the effect of OB/BOS on CRV, landmark plots were generated at specific time points. Time to development of OB/BOS was then compared using the Kaplan-Meier method., Results: In our institution, we documented 40 infections caused by CRV in 33 lung transplant recipients during an 11-year period. Community respiratory virus infections occurred predominantly during seasonal community outbreaks, except for parainfluenza infections, which occurred throughout the year. The diagnosis of OB/BOS occurred throughout the year and was not associated with seasonal outbreaks of CRV. Community respiratory virus infection involving both upper and lower respiratory tracts did not predispose to OB or BOS (relative risk [RR], 1.1; 95% confidence interval [CI], 0.52-2.3; p = 0.81). However, patients with documented CRV infection of the lower respiratory tract were predisposed to high-grade BOS development (RR, 2.3; 95% CI, 1.1-4.9; p = 0.04). In addition, a patient with pre-existing OB or BOS was predisposed to developing both upper and lower respiratory tract infection with CRV (RR, 4.2; 95% CI, 1.9-9.4; p < 0.001)., Conclusions: Patients with CRV infection of the lower respiratory tract were predisposed to high-grade BOS development, and patients with OB and BOS were predisposed to CRV infections.

Respiratory infections remain a significant cause of morbidity and mortality after lung transplantation. In addition to cytomegalovirus, the community respiratory viruses such as respiratory syncytial virus (RSV), parainfluenza virus (PIV), influenza virus, and adenovirus, are important causes of infection in transplant recipients, often involve the lower respiratory tract, and may be associated with significant morbidity and mortality. In this review, we summarize the current state of knowledge regarding the epidemiology, clinical manifestations, diagnosis, treatment and outcomes associated with RSV, PIV, influenza virus, and adenovirus infections in lung transplant recipients.

Purposes: The purpose of this study was to describe complementary and alternative medicine (CAM) use by lung transplant patients and to determine whether CAM users differ from nonusers with respect to health status, quality of life, or medical adherence., Methods: A mailed survey seeking CAM, quality of life, and adherence information was sent to 145 lung transplant recipients, and 99 responded., Results: The majority (88%) used at least 1 form of CAM (median, 2; range, 0-17). Prayer (68%), support groups (43%), and relaxation techniques (31%) were the most common. Only 44% of users reported discussing CAM with their providers. CAM users were adherent to their transplant regimen. Few differences were found between CAM users and nonusers. Education, high symptom burden, female sex, and depression symptoms were associated with various types of CAM use., Conclusion: Most lung transplant recipients are using CAM. Providers must explore potential for interaction or enhancement between CAM and standard therapy to optimize care.

Background: RAD is a novel macrolide with potent immunosuppressive and antiproliferative activities. This study characterizes the safety, tolerability, and pharmacokinetics of two different single oral doses of RAD in stable lung and heart/lung transplant recipients with and without cystic fibrosis (CF)., Methods: This was a Phase I, multicenter, randomized, double-blind, two-period, two-sequence, crossover study. Single doses of RAD capsules at doses of 0.035 mg/kg (2.5 mg maximum) or 0.10 mg/kg (7.5 mg maximum) were administered with cyclosporine (Neoral [cyclosporine, USP] modified), steroids, and azathioprine on Day 1. The alternate dose was administered on Day 16. Laboratory assessments, vital signs, and adverse events were recorded throughout the study. RAD pharmacokinetic profiles were assessed over a 7-day period following each dose. Steady-state cyclosporine (CsA) profiles were assessed at baseline and with each RAD dose; RAD and CsA trough concentrations were obtained throughout the study period., Results: Of the 20 patients randomized, 8 had CF and 12 did not. Single doses of RAD were safe and well tolerated. Headache was the most common side effect. RAD produced a mild, dose-dependent, reversible decrease in platelet and leukocyte counts. Cholesterol and triglycerides were minimally affected. At both doses, CF patients had significantly lower peak concentrations of RAD than did non-CF patients (p = 0.03); however, overall exposure (area under the curve/dose) was not different between the groups (p = 0.63). At the higher dose, there was a clinically minor under-proportionality in AUC, averaging -11%. Steady-state pharmacokinetics of CsA were not affected by RAD co-administration.RAD was safe and well tolerated by stable lung and heart/lung transplant recipients with and without CF. The presence of CF did not influence the extent of RAD exposure. Single doses of RAD did not affect the pharmacokinetics of CsA. Ongoing studies are assessing the long-term safety and efficacy of RAD in lung and heart/lung transplantation.

Background: The early experience of lung transplantation was plagued with airway anastomotic complications. The use of corticosteroids in the pre-transplant period has been implicated as a major contributing factor in bronchial dehiscence, and many patients have been denied transplantation on the basis of corticosteroid use. We conducted the current study to assess the risks associated with pre-transplant corticosteroid use., Methods: We analyzed records of 73 single- and bilateral-single lung transplant recipients who had chronic obstructive pulmonary disease or alpha(1)-antitrypsin deficiency as their underlying disease from 1986 to 1996. Twenty-six patients (steroid group) received daily corticosteroid therapy (prednisone, 1.5 to 40 mg/day) up to the time of transplantation, whereas 47 patients did not receive chronic corticosteroids and had no corticosteroid therapy within 3 months of transplantation (non-steroid group)., Results: The demographic profiles of the 2 groups were comparable. We noted no statistical significances in length of hospital stay, duration of intensive care, and post-operative pulmonary function. The rates of cytomegalovirus infection, acute rejection, bronchiolitis obliterans syndrome, and survival were also similar. The non-steroid group seemed to have a higher rate of bronchial stenosis at 3 years (29% vs 6%, p = 0.03). Bronchial dehiscence did not occur in either study group., Conclusions: Pre-transplant use of corticosteroids does not adversely affect outcome following lung transplantation.

Based on data reported to the UNOS/ISHLT Thoracic and International Registry for Thoracic Organ Transplantation: 1. The number of heart transplant operations performed in the United States decreased between 1998-1999 and 17 (1%) more procedures were performed in 1999 (2,181) than in 2000 (2,198). Sixty-nine more lung transplants (an 8% increase) were reported in 2000 than in 1999. 2. Coronary artery disease and cardiomyopathy were the most frequently cited indications for heart transplantation in the US and have been reported at similar rates during the past 10 years. Combined, these diagnoses account for approximately 85% of all heart transplants. In 2000, half of all lung transplants were performed for emphysema/COPD or alpha-1 antitrypsin deficiency. The most frequently reported diagnoses for thoracic transplantation outside the US were: cardiomyopathy (49%) for heart, cystic fibrosis (30%) for double lung, emphysema/COPD (34%) for single lung and primary pulmonary hypertension (21%) for heart-lung transplants. 3. US heart transplant recipients were predominately male (76%), aged 50-64 (51%) and white (81%). US lung transplant recipients were also predominately between ages 50-64 (47%) and white (90%), but unlike heart recipients were more likely to be female (51%). No meaningful variance from the US recipient demographic profile was noted for the non-US recipients during the same time period. 4. Pediatric recipients (< 18 years of age) received 11% of the reported heart transplants and 6% of the reported lung transplants in the US. 5. Among US thoracic transplant recipients during 1999, the one-year survival rates were 84% for heart, 59% for heart-lung and 77% for lung. The 5-year survival rates for transplants performed during 1995 were: 71% for heart, 56% for heart-lung and 44% for lung transplants. 6. The long-term patient survival rates were: 23% at 19 years for heart, 16% at 11 years for lung and 23% at 14 years for heart-lung recipients. 7. During the first year after transplantation, 66% of heart recipients and 44% of lung recipients did not require rehospitalization. Among those recipients who were rehospitalized, the major cause was infection.

7 days) failure. Seven (78%) patients in the early group were weaned off ECMO and 5 (56%) survived to hospital discharge. In the late group, none of the patients could be weaned off ECMO, yielding 100% mortality. ECMO support instituted for pulmonary graft failure that occurred within 24 hours of transplantation may improve patient survival.

Objectives: To compare the detection of bronchiolitis obliterans syndrome (BOS) in lung transplant recipients by clinic pulmonary function laboratory measurement and home spirometry., Design: The subjects served as their own control group., Setting: A university-based thoracic transplant center., Subjects: Forty-five lung transplant recipients (26 women and 19 men; average +/- SD age, 47.7+/-11.4 years old at the time of transplantation). Lung function declined to at least BOS stage 1 in 17 of the 45 subjects., Measurements: All subjects were participants in a home monitoring program utilizing home spirometry measurements. Clinic spirometry and home spirometry measurements were collected concurrently. The determinations of BOS staging were based on home and clinic FEV1 values using retrospective analysis and development of the home-based BOS staging algorithm., Results: BOS stage 1 was detected an average of 341 to 276 days earlier with home spirometry than with clinic pulmonary function testing in the 17 subjects who had a pulmonary decline to BOS stage 1, depending on the persistence of the decline (1 day or 3 days, respectively). The difference in BOS detection time was statistically significant for both persistence requirements (p < 0.001)., Conclusions: Home spirometry detects pulmonary decline earlier than clinic spirometry; home spirometry can be a reliable and safe alternative to frequent pulmonary function testing in lung recipients.

Background: Extracorporeal photopheresis is an immunomodulatory technique in which a patient's leukocytes are exposed to ultraviolet-A light after pretreatment with 8-methoxypsoralen (methoxsalen). There have been few reports describing the use of extracorporeal photopheresis in lung transplant recipients., Methods: We reviewed our experience using extracorporeal photopheresis in 8 lung transplant recipients since 1992. All 8 patients had progressively decreasing graft function and 7 were in bronchiolitis obliterans syndrome grade 3 before the initiation of photopheresis. One patient had undergone a second transplant operation for obliterative bronchiolitis. Two patients had a pretransplantation diagnosis of chronic obstructive pulmonary disease, 1 alpha1-antitrypsin deficiency, 1 cystic fibrosis, 1 bronchiectasis, 1 idiopathic pulmonary fibrosis, and 2 primary pulmonary hypertension. Before refractory rejection developed, all patients had been treated with 3-drug immunosuppression and anti-T-cell therapy. The median time from transplantation to the start of extracorporeal photopheresis was 16.5 months and the median number of treatments was 6., Results: The condition of 5 of 8 patients subjectively improved after extracorporeal photopheresis therapy. In these 5 patients photopheresis was associated with stabilization of the forced expiratory volume in 1 second. In 2 patients there was histologic reversal of rejection after photopheresis. With a median follow-up of 36 months, 7 patients are alive and well. Three patients required retransplantation at a median of 21 months after completion of the treatments. Four patients have remained in stable condition after photopheresis. There were no complications related to extracorporeal photopheresis., Conclusion: We believe that this treatment is a safe option for patients with refractory lung allograft rejection when increased immunosuppression is contraindicated or ineffective.

Background: One third of human lung allografts develop chronic rejection manifested as obliterative bronchiolitis. Heterotopically transplanted allogeneic murine tracheas develop obliterative airway disease (OAD) leading to a lesion resembling human obliterative bronchiolitis. The purpose of this study was to determine the T-cell and major histocompatibility complex (MHC) molecule requirements of murine OAD., Methods: BALB/c allografts and C57BL/6 (B6) isografts were transplanted into B6 severe combined immunodeficient (SCID) and B6 wild-type (WT) recipients. MHC class I-discrepant bm1 grafts, class II-discrepant bm12 grafts, and F1(bm1 x bm12) (F1) grafts also were transplanted into B6 WT recipients. Grafts were harvested between days 5 and 56 following transplantation and evaluated histologically., Results: Complete MHC-disparate allografts placed in WT recipients had significantly more disease than similar allografts in SCID recipients, and the latter were indistinguishable from isografts in either WT or SCID recipients, indicating a lymphocyte dependence on the disease development. Pathology was significantly more severe in bm1 and F1 allografts than in isografts recovered from B6 recipients, but bm12 allografts appeared no different than isografts. T-cell infiltrates in these bm12 allografts contained only CD4+ cells, whereas infiltrates in the BALB/c, bm1, and F1 allografts manifesting OAD contained both CD4+ and CD8+ cells. No grafts had significant B-cell infiltration., Conclusions: These findings suggest that OAD relies on a host T-cell response that includes CD8+ cells, directed against allo-class I-bearing donor cells within the graft.

Background: Cytomegalovirus is an important cause of morbidity and mortality risk after lung transplantation. Ganciclovir, when given for a period of up to 3 months after lung transplantation, has been shown to reduce the incidence and severity of cytomegalovirus. However, daily prophylaxis is associated with considerable expense, inconvenience, and morbidity risk. The goal of this study was to determine whether 3-times-weekly dosage is as effective as daily prophylaxis with ganciclovir in preventing cytomegalovirus disease., Methods: Seventy-two consecutive subjects who had either donor or recipient cytomegalovirus seropositivity were randomized to the daily group (n = 35) or the 3-times-weekly group (n = 37). All subjects received twice-daily ganciclovir treatment for 2 weeks. Thereafter, subjects received either daily or 3-times-weekly ganciclovir dosing until 90 days after transplantation. Subjects were then monitored for 28 +/- 13 months to identify outcomes and complications., Results: There were no significant differences between the daily and 3-times-weekly groups with respect to survival free from cytomegalovirus infection or survival free from cytomegalovirus disease. In both groups, cytomegalovirus infection and disease frequently emerged after the termination of prophylaxis. However, in most cases the cytomegalovirus syndromes observed were mild and in many cases could be treated on an outpatient basis. There was no significant difference between the groups in the incidence of obliterative bronchiolitis or time to onset of grade 2 bronchiolitis obliterans syndrome. Overall patient survival was better in the daily group, but the survival advantage did not appear to be related to a reduction in cytomegalovirus-related disease. Complications of ganciclovir prophylaxis included leukopenia in 2 subjects in the 3-times-weekly group and catheter-related sepsis in 6 subjects from each group., Conclusions: We conclude that intravenous ganciclovir given 3 times weekly for 3 months after transplantation is as effective as daily ganciclovir given for a similar time period. The 3-times-weekly dosing regimen did not result in increased infection, disease, or sequelae of cytomegalovirus infection when compared with the daily regimen.

Background: Organ donors and transplant recipients are routinely tested for ABO compatibility. ABO-identical organs are preferred, but occasionally the use of an ABO-compatible but nonidentical donor is clinically warranted. In heart-lung transplantation, the incidence of hemolysis from donor-derived anti-ABO antibodies is as high as 70%. The incidence of hemolysis for lung-only transplantation is not known. Our current posttransplantation transfusion policy for ABO-compatible but nonidentical lung-only transplant recipients is, when indicated, to use donor ABO group red blood cells., Methods: To evaluate the efficacy of our transfusion policy, we reviewed our experience from 1986-96. One heart-lung transplant, four single lung transplant, and three bilateral single lung transplant recipients received ABO-compatible but nonidentical organs., Results: The heart-lung transplant recipient developed a positive direct antiglobulin test (DAT), with anti-A eluted, and severe hemolysis on postoperative day 8 requiring plasma and whole blood exchange. Four of six lung-only transplant patients tested developed a positive DAT with anti-A eluted. Two early lung-only patients, who did not receive donor ABO group red blood cells, demonstrated clinical and laboratory evidence of hemolysis. Three bilateral lung transplant recipients were followed prospectively. The first patient had a negative DAT. The next two patients developed positive DATs on postoperative day 8 and 10, respectively. No evidence of hemolysis was detected in any of these cases., Conclusions: These results confirm that donor-derived anti-ABO antibodies develop with lung-only transplants. Our current transfusion policy is justified for both heart-lung and lung recipients of ABO-compatible but nonidentical organs. A high index of suspicion for donor-derived antibody causing hemolysis and communication with blood bank personnel are mandatory in this setting.

Background: Invasive Aspergillus is an important cause of morbidity and mortality among lung transplant recipients. The diagnosis can be difficult and treatment is often unsuccessful so many centers preemptively treat all Aspergillus airway isolates to prevent invasive disease. This approach is untested as little is known about the relationship between Aspergillus airway colonization and invasive disease. This study was undertaken to evaluate the incidence of Aspergillus airway colonization after lung transplantation and the risk of invasive disease after colonization., Design: All cultures and histologic specimens obtained from a consecutive series of 151 lung transplant cases were reviewed for the presence of Aspergillus and compared with clinical data., Results: Aspergillus was isolated from the airway in 69 (46%) of 151 transplant recipients. Invasive disease occurred in five cases and was uniformly fatal, accounting for 13% of all posttransplant deaths. Results of cytologic examination of BAL fluid were normal in all cases of invasive disease and cultures were positive in only one of five patients prior to invasion. Invasive disease occurred exclusively in patients who died or were colonized with Aspergillus fumigatus within the first 6 months posttransplant. Patients growing A. fumigatus from the airway during the first 6 months were 11 times more likely to develop invasive disease relative to those not colonized., Conclusion: Aspergillus airway colonization after lung transplantation is common and in most cases, transient. In contrast, invasive Aspergillus disease is less common, but fatal. Bronchoscopy with cytologic examination and fungal culture are not sensitive or timely predictors of invasive disease. Invasive Aspergillus occurred only in patients initially colonized with A. fumigatus within the first 6 months posttransplant. A trial of empiric anti-Aspergillus therapy limited to the first 6 months posttransplant may be warranted.

Objective: This study identifies specific clinical and immunologic factors in lung transplant recipients that influence the subsequent development of chronic allograft dysfunction., Methods: The study group consisted of 132 consecutive patients who received lung allografts (76 single, 25 bilateral single, and 31 heart-lung) and survived at least 90 days. One hundred twenty-one patients were used in the analysis that modeled time to development of histologic obliterative bronchiolitis or bronchiolitis obliterans syndrome., Results: Variables noted to have an effect on the time to development of bronchiolitis obliterans syndrome included cytomegalovirus pneumonitis (RR = 3.2, p = 0.001), late acute rejection (RR = 1.3, p = 0.02), human leukocyte antigen mismatches at the A loci (RR = 1.8, p = 0.02), total human leukocyte antigen mismatches (RR = 1.4, p = 0.04), and absence of donor antigen-specific hyporeactivity (52% vs 100% survival free from bronchiolitis obliterans syndrome at 2 years; p = 0.005). Cytomegalovirus pneumonitis had a significant effect on time to obliterative bronchiolitis (RR = 3.6, p = 0.0005), as did donor antigen-specific hyporeactivity (52% vs 100% survival free from obliterative bronchiolitis at 2 years; p = 0.01). In multivariate analysis, cytomegalovirus pneumonitis (RR = 3.2, p = 0.02), human leukocyte antigen mismatches at the A loci (RR = 2.4, p = 0.006), and late acute rejection (RR = 1.3, p = 0.02) were identified as predictors of bronchiolitis obliterans syndrome. Cytomegalovirus pneumonitis was associated with time to development of histologic obliterative bronchiolitis (RR = 2.3, p = 0.02)., Conclusions: Several risk factors were associated with the development of chronic allograft dysfunction, which, in turn, had a significant impact on long-term survival. Early identification of lung allograft recipients with risk factors for the development of bronchiolitis obliterans syndrome may allow modification in immunosuppression and antiviral therapy to potentially decrease the prevalence of this disorder.

Obliterative bronchiolitis following lung transplantation is common and potentially devastating. Its exact cause is undefined, but multiple immune and nonimmune processes contribute to its pathogenesis. Severe acute rejection and recurrent acute rejection have been shown to confer the greatest risk for obliterative bronchiolitis, signifying the central importance of alloimmunity in the disease process. Treatment of established disease with intensification of immune suppression has been of limited benefit, so current clinical strategies include early detection and minimization of risk. As our understanding of the disease evolves, it is hoped that effective interventions targeted at specific pathogenetic steps will emerge. In the meantime, obliterative bronchiolitis remains the most important and sinister long-term complication of lung transplantation.

Background: Airway anastomosis complications continue to be a source of morbidity for lung transplant recipients., Methods: This study analyzes incidence, treatment, and follow-up of airway anastomotic complications occurring in 127 consecutive lung transplant airway anastomoses (77 single lung and 25 bilateral sequential lung). Complications were categorized as stenosis (11), granulation tissue (8), infection (7), bronchomalacia (5), or dehiscence (3). Follow-up after treatment ranged from 6 months to 4 years., Results: Nineteen airway anastomosis complications (15.0%) occurred in 18 patients. Telescoping the airway anastomosis reduced the complication rate to 12 of 97 (12.4%), compared with 7 of 30 (23.3%) for omental wrapping, (p = 0.15). Complications developed in 13 of 77 single-lung airway anastomoses (16.9%) versus 6 of 50 bilateral sequential lung recipients (12.0%). Treatment consisted of stenting (9 airway anastomoses), bronchodilation (8), laser debridement (4), rigid bronchoscopic debridement (2), operative revision (2), and growth factor application (2). There was no difference in actuarial survival between patients with or without airway anastomosis complications (p = 1.0)., Conclusions: Airway anastomosis complications can be successfully managed in the immediate or late postoperative period with good outcome up to 4 years after intervention.