John P. Lynch

HLA-A locus mismatches and development of antibodies to HLA after lung transplantation correlate with the development of bronchiolitis obliterans syndrome

BACKGROUND Bronchiolitis obliterans syndrome (BOS) is the most common cause of morbidity and mortality after lung transplantation (LT). A retrospective analysis of clinical and immunologic variables were done to identify those that might predict the development of BOS. METHODS Of 112 LT performed over a 42-month interval, 94 survived at least 3 months and form the basis of this analysis. There was a minimum of 21 months follow-up. BOS was defined on the basis of declining spirometry (FEV1 <80% of baseline) and/or the presence of histologic obliterative bronchiolitis. All variables analyzed were subjected first to a univariate analysis; those variables appearing to carry significance were then subjected to a multivariate logistic regression analysis. RESULTS Univariate analysis revealed the following to be predictors of the development of BOS: age (the probability of developing BOS declined with advancing age); donor/recipient HLA-A locus mismatch, with actuarial freedom from BOS being significantly greater with no A-locus mismatches versus cases with one or two mismatches (P=0.031); and development of anti-HLA antibodies after transplantation (P=0.006 vs. recipients without detectable antibodies). In multivariate analysis, only HLA locus mismatch and development of anti-HLA antibodies were significant independent predictors of the development of BOS. The remaining clinical variables (gender, type of LT, indication for LT, graft ischemic time, use of cardiopulmonary bypass, cytomegalovirus) and immunologic variables (crossmatch, frequent early acute rejection) did not correlate with the development of BOS. CONCLUSIONS These data suggest that BOS is the result of an immune process, that differences at the HLA-A locus may play an important role in this process, and antibody-mediated injury may play a role in BOS.

Development of ELISA-detected anti-HLA antibodies precedes the development of bronchiolitis obliterans syndrome and correlates with progressive decline in pulmonary function after lung transplantation.

BACKGROUND Development of anti-HLA antibodies after lung transplantation (LT) is thought to play an important role in the etiology of bronchiolitis obliterans syndrome (BOS). However, a cause-effect relationship between anti-HLA antibodies and BOS has not been established. This study was conducted to determine the temporal relationship between the development of anti-HLA antibodies and BOS after LT, and to determine the antigenic specificity of the antibodies developed in BOS patients. METHODS Sera from 15 BOS+ LT patients and 12 BOS- LT patients were obtained before LT and collected again at 6, 12, 24, 36, and 48 months after LT. Anti-HLA antibodies were detected by the PRA-STAT ELISA system and by complement-dependent cytotoxicity assays. Anti-HLA reactivity was further characterized by flow cytometry and absorption/elution with human platelets. RESULTS When analyzed by ELISA, 10 of 15 BOS+ patients developed anti-HLA antibodies, whereas 0 of 12 BOS- patients developed anti-HLA antibodies (P<0.001). When analyzed by complement-dependent cytotoxicity, only 2 of 15 BOS+ patients developed anti-HLA antibodies and 1 of 12 BOS- patients developed anti-HLA antibodies (P = 0.99). There was a significant difference of 20.1 months between the time of anti-HLA antibody detection and the time of BOS diagnosis (P = 0.005). A progressive decrease in pulmonary function correlated with a progressive increase in the anti-HLA reactivity 36 months after LT. The anti-HLA reactivity was directed to one of the donor HLA class I antigens and to other unrelated HLA class I antigens. No anti-HLA reactivity was found against HLA class II molecules. CONCLUSIONS Our study indicates that anti-HLA class I antibodies play an important role in the pathogenesis of BOS and that monitoring of anti-HLA class I antibody development by a highly sensitive assay such as the PRA-STAT ELISA after LT can provide an early identification of an important subset of LT patients with an increased risk of developing BOS.

Lung Transplantation: A Decade of Experience

OBJECTIVE To review the 10-year clinical experience of a single institutions adult lung transplant program. METHODS Since July 1988, 450 lung transplants have been performed in 443 patients. Recipient diagnoses included emphysema in 229 patients, cystic fibrosis in 70 patients, pulmonary fibrosis in 48 patients, pulmonary hypertension in 49 patients, and miscellaneous end-stage lung diseases in 47 patients. Single-lung transplant was performed in 157 cases, bilateral sequential lung transplant in 283 cases, en bloc double-lung transplant in 8 cases, and heart-lung transplant in 2 cases. Graft lungs were obtained from local donors in 24% of cases and from distant donors in 76% of cases. Ideal donors were used in 74% of cases; in 26%, the donor was classified as marginal based on objective criteria. RESULTS Four hundred six (91.6%) lung transplant recipients survived to hospital discharge. There were 37 hospital deaths from cardiac events (n = 8), primary graft failure (n = 8), sepsis (n = 6), anastomotic dehiscence (n = 6), and other causes (n = 9). A diagnosis of chronic rejection (bronchiolitis obliterans syndrome [BOS]) was made in 191 patients (42.5%). BOS has not been improved by any specific therapy. Rates of freedom from BOS at 1, 3, and 5 years after the transplant are 82%, 42%, and 25%. One-, 3-, and 5-year actuarial survival rate for the entire group are 83%, 70%, and 54%. There is no statistical difference in survival according to diagnosis or type of lung transplant. Recipient waiting time was 116 days in the first 90 patients and 634 days in the most recent 90 patients. CONCLUSIONS Lung transplantation offers patients with end-stage lung disease acceptable prospects for 5-year survival. Chronic rejection and long waiting lists for donor lungs continue to be major problems facing lung transplant programs. The use of marginal and distant donors is a successful strategy in improving donor availability.

Indirect recognition of donor HLA class I peptides in lung transplant recipients with bronchiolitis obliterans syndrome.

BACKGROUND The presentation of donor MHC class II-derived peptides by host antigen-presenting cells in the context of self-MHC class II molecules has been suggested as a mechanism for the chronic rejection of kidney and heart allografts. The aim of this study was to determine whether indirect allorecognition of HLA class I-derived peptides occurred in lung transplant (LTx) recipients and whether it correlated with the development of bronchiolitis obliterans syndrome (BOS). METHODS Peripheral blood mononuclear cells from LTx recipients were cultured with synthetic peptides corresponding to the hypervariable regions of the mismatched HLA class I antigens of the donor. Proliferation and precursor frequency (PF) of allopeptide reactive T cells were determined by the incorporation of [3H]thymidine into DNA and limiting dilution analysis. RESULTS Peripheral blood leukocytes of LTx recipients with BOS mismatched for HLA class I molecules showed a proliferative response three- to fourfold higher than those observed in mismatched recipients without BOS and in normal control individuals (P<0.001). Similarly, the PF of allopeptide-reactive T cell was 3- to 24-fold higher in recipients with BOS compared with recipients without BOS (P<0.05) as well as normal control individuals (P<0.03). The T cell PF to donor-specific allopeptides, as well as irrelevant allopeptides, was not significantly different in LTx recipients without BOS and normal control individuals. CONCLUSIONS These data suggest that T cells from LTx recipients are sensitized to mismatched HLA class I antigens. The sensitization was significantly higher in LTx recipients with BOS compared with LTx recipients without BOS. Strategies to block T-cell responses generated by indirect allorecognition after lung transplantation may provide a means for the prevention or treatment of BOS in LTx recipients.

Thirteen-year experience in lung transplantation for emphysema.

BACKGROUND Emphysema is the most common indication for lung transplantation. Recipients include younger patients with genetically determined alpha-1 antitrypsin deficiency (AAD) and, more commonly, patients with chronic obstructive pulmonary disease (COPD). We analyzed the results of our single-institution series of lung transplants for emphysema to identify outcome differences and factors predicting mortality and morbidity in these two groups. METHODS A retrospective analysis was undertaken of the 306 consecutive lung transplants for emphysema performed at our institution between 1988 and 2000 (220 COPD, 86 AAD). Follow-up was complete and averaged 3.7 years. RESULTS The mean age of AAD recipients (49 +/- 6 years) was less than those with COPD (55 +/- 6 years; p < 0.001). Hospital mortality was 6.2%, with no difference between COPD and AAD, or between single-lung transplants and bilateral-lung transplants. Hospital mortality during the most recent 6 years was significantly lower (3.9% vs 9.5%, p = 0.044). Five-year survival was 58.6% +/- 3.5%, with no difference between COPD (56.8% +/- 4.4%) and AAD (60.5% +/- 5.8%). Five-year survival was better with bilateral-lung transplants (66.7% +/- 4.0%) than with single-lung transplants (44.9% +/- 6.0%, p < 0.005). Independent predictors of mortality by Cox analysis were single lung transplantation (relative hazard = 1.98, p < 0.001), and need for cardiopulmonary bypass during the transplant (relative hazard = 1.84, p = 0.038). CONCLUSIONS AAD recipients, despite a younger age, do not achieve significantly superior survival results than those with COPD. Bilateral lung transplantation for emphysema results in better long-term survival. Accumulated experience and modifications in perioperative care over our 13-year series may explain recently improved early and long-term survival.

Cardiac and pulmonary replacement Single or bilateral lung transplantation for emphysema

Abstract Background: Most programs favor single lung transplantation for emphysema. However, this is controversial, and we have favored bilateral lung transplantation, confining single lung transplantation mainly to use in older patients and those of small stature. Methods: A retrospective analysis was done of 119 consecutive lung transplantation procedures for emphysema at Barnes Hospital between 1989 and 1994 (50 single lung, 69 bilateral lung transplants) to (1) identify outcome differences between the two groups and (2) define the appropriate role of these two procedures. Results: The single lung transplantation group was older and had a higher proportion of female patients. However, baseline pulmonary function (forced expiratory volume in 1 second), arterial oxygen tension, and exercise tolerance (6-minute walk distance) were similar. After transplantation, 90-day mortality (single lung transplantation 10% versus bilateral lung transplantation 7.2%; p = 0.74) and duration of mechanical ventilation, intensive care unit stay, and hospitalization were similar. Both groups achieved a significant and sustained improvement in forced expiratory volume, arterial carbon dioxide tension, arterial oxygen tension, and exercise tolerance within 3 months. However, the improvements in forced expiratory volume, arterial oxygen tension, and exercise tolerance were consistently significantly better in recipients of bilateral transplants at and beyond 6 months. Obliterative bronchiolitis was equally prevalent in both groups. Survival was similar but showed a trend toward better late survival in recipients of bilateral transplants (5-year actuarial survival: bilateral lung transplantation 53% versus single lung transplantation 41%). Conclusions: We conclude that (1) both procedures are satisfactory options in emphysema, producing durable results; (2) bilateral lung transplantation is not associated with increased operative mortality or morbidity and achieves superior improvements in spirometry findings, oxygenation, exercise tolerance, and possibly late survival; and (3) the superior improvements in function (and late survival) after bilateral lung transplantation may be attributed to the presence of more pulmonary reserve after the onset of obliterative bronchiolitis. (J Thorac Cardiovasc Surg 1996;112:1485-95)

Lung transplantation for pulmonary vascular disease

BACKGROUND Pulmonary hypertension (PHT) is a lethal condition resulting in markedly diminished life expectancy. Continuous prostaglandin I2 infusion has made an important contribution to symptom management, but it is not a panacea. Lung or heart-lung transplantation remains an important treatment option for end-stage PHT patients unresponsive to prostaglandin I2. This study reviews the outcomes after transplantation for PHT in our program. METHODS A retrospective chart review was performed for 100 consecutive patients with either primary PHT (48%) or secondary PHT (52%) transplants since 1989. Living recipients were contacted to confirm health and functional status. RESULTS Fifty-five adult and 45 pediatric patients underwent 51 bilateral lung transplants, 39 single lung transplants, and 10 heart-lung transplants. Mean age was 23.7 years (range, 1.2 months to 54.8 years) and mean pre-transplant New York Heart Association class was 3.2. Pre-transplant hemodynamics revealed a mean right atrial pressure of 9.6+/-5.4 mm Hg and mean pulmonary artery pressure of 64+/-14.4 mm Hg. Hospital mortality was 17% with early death predominantly because of graft failure and infection. With an average follow-up of 5.0 years, 1- and 5-year actuarial survival was 75% and 57%, respectively. Mean pulmonary artery pressure on follow-up catheterization was 22+/-6.0 mm Hg, and mean follow-up New York Heart Association class was 1.3 (p < 0.001 for both compared with pre-transplant). Diagnosis and type of transplant did not confer a significant difference in survival between groups. CONCLUSIONS Whereas lung or heart-lung transplant for PHT is associated with higher early mortality than other pulmonary disease entities, it provides similar long-term outcomes with dramatic improvement in both quality of life and physiologic aspects.

Lymphoproliferative disease after lung transplantation : Comparison of presentation and outcome of early and late cases

BACKGROUND Post-transplantation lymphoproliferative disease (PTLD) after lung transplantation has not been fully characterized. In previous studies, the incidence has varied substantially, and most cases have been reported during the first year after transplantation. The purpose of this study was to review our centers experience with PTLD and to analyze the pattern of disease and determinants of outcome. METHODS Among 494 adult lung (n = 491) or heart-lung (n = 3) recipients, 30 cases of PTLD were retrospectively identified. The cases were classified by site(s) of involvement, histology and time of onset (early, < or =1 year, and late, >1 year after transplantation). The outcome of each case was ascertained, and risk factors for death were analyzed in a multivariate model. RESULTS PTLD was identified in 30 (6.1%) of the recipients during 1,687 patient-years (median 2.8 years) of follow-up. The incidence density was 1.8 cases per 100 patient-years. Fourteen cases were diagnosed during the first year after transplantation, and 16 cases in subsequent years. The incidence density was significantly higher in the first year than in later years (3.3 cases/100 patient-years versus 1.3 cases/100 patient years; p <.008). Presentation in the thorax and involvement of the allograft were significantly more common in the early cases (thorax: 12 of 14, 86%; allograft: 9 of 14, 64%) than in the late cases (thorax: 2 of 16, 12%; allograft: 2 of 16, 12%). There was no difference in survival after the diagnosis of PTLD between the early and late cases, but survival time after diagnosis was significantly longer in cases with, than those without, allograft involvement (median 2.6 years vs 0.2 year, respectively; log rank p = 0.007). The presentation and pattern of organ involvement of PTLD after lung transplantation is related to the time of onset. CONCLUSIONS Disease in the thorax and involvement of the allograft are common in the first year after transplantation, but other sites, especially the gastrointestinal tract, predominate later. PTLD that is confined to the allograft appears to have a somewhat better prognosis than disease that involves other sites.

The impact of ganciclovir-resistant cytomegalovirus infection after lung transplantation.

BACKGROUND Cytomegalovirus (CMV) resistance to ganciclovir has become increasingly common in acquired immunodeficiency syndrome patients but has only rarely been reported in recipients of solid organ transplants. METHODS A retrospective study of ganciclovir susceptibility testing of CMV isolates recovered from lung transplant recipients was performed. Patients with CMV isolates having partial (1 or =3 microg/ml) to ganciclovir determined by plaque reduction assay were included in a case-control study to identify risk factors for ganciclovir resistance. RESULTS Between 2/91 and 5/98, 18 patients (5.2% of patients transplanted) were found to have CMV infections with some degree of ganciclovir resistance (4 partially, 14 fully resistant). More positive viral blood cultures (3.2+/-2.5 vs. 1.6+/-1.4 CMV positive cultures, P=0.02) and more episodes of CMV pneumonitis (0.24+/-0.23 vs. 0.10+/-0.17 episodes/bronchoscopy, P=0.02) occurring before the detection of resistance were seen among resistant patients than controls. Ganciclovir-resistant patients received more antithymocyte globulin during induction (70+/-44 vs. 45+/-39 mg/kg, P=0.03) and received ganciclovir for a greater number of days (79+/-52 vs. 64+/-53 days, P=0.005) before the detection of resistance than controls. Ganciclovir-resistant patients had a shorter survival and an earlier onset of bronchiolitis obliterans syndrome compared with patients in the transplant database at Washington University. CONCLUSIONS Ganciclovir-resistant CMV infection is a serious complication of solid organ transplantation associated with more episodes of viremia, more frequent disease, earlier onset of bronchiolitis obliterans and shorter survival. The use of antithymocyte globulin and prolonged exposure to ganciclovir are risk factors for the development of ganciclovir resistance.

Efficacy of total lymphoid irradiation for chronic allograft rejection following bilateral lung transplantation

PURPOSE To assess the safety and efficacy of total lymphoid irradiation (TLI) in patients experiencing chronic rejection following bilateral lung transplantation (BLT). PATIENTS AND MATERIALS Eleven patients received TLI for chronic allograft rejection (bronchiolitis obliterans syndrome) refractory to conventional treatment modalities. Radiation therapy (RT) was prescribed as 8 Gy delivered in 10 0.8-Gy fractions, 2 fractions/week, via mantle, paraaortic, and inverted-Y fields. Serial pre- and post-RT pulmonary function values, complete blood counts, and immunosuppressive augmentation requirements [use of methylprednisolone, murine anti-human mature T-cell monoclonal antibody (OKT3), polyclonal antithymocyte globulin (ATG), and tacrolimus] were monitored. RESULTS In the 3 months preceding TLI, the average decrease in forced expiratory volume in 1 s (FEV1) was 34% (range 0-75%) and the median number of immunosuppression augmentations was 3 (range 0-5). Only 4 of 11 patients completed all 10 TLI treatment fractions. Reasons for discontinuation included progressive pulmonary decline (four patients), worsening pulmonary infection (two patients), and persistent thrombocytopenia (one patient). Seven of the 11 patients failed within 8 weeks of treatment cessation. One patient had unabated rejection and received bilateral living related-donor transplants; he is alive and well. Six patients died. Two of these deaths were due to pulmonary infection from organisms isolated prior to the start of RT; the other four deaths were from progressive pulmonary decline. The four remaining patients had durable positive responses to TLI (mean follow-up of 47 weeks; range 24-72). Comparing the 3 months preceding RT to the 3 months following treatment, these four patients had improvements in average FEV1 (40% decline vs. 1% improvement) and fewer median number of immunosuppressive augmentations (3.5 vs. 0). None of these patients has developed lymphoproliferative disease or has died. Features suggestive of a positive response to TLI included longer interval from transplant to RT, higher FEV1 at initiation of RT, and absence of preexisting pulmonary infection. CONCLUSION Total lymphoid irradiation for chronic allograft rejection refractory to conventional medical management following BLT was tolerable. A subset of patients experienced durable preservation of pulmonary function and decreased immunosuppressive requirements. Patients with rapidly progressive allograft rejection, low FEV1, or preexisting infection were least likely to benefit from irradiation. Early initiation of TLI for patients experiencing chronic allograft rejection following BLT may be warranted.