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The social rehabilitation of lung transplant recipients becomes increasingly important as the results of lung transplantation improve. Although return-to-work (RTW) rates have been published for recipients of other organ transplants, no such data are available after lung transplantation. The purpose of this study was to determine what factors influence RTW after lung transplantation. Of 99 lung transplant recipients (43 single, 56 bilateral) surveyed from Denver, Colorado, (n = 49) and Toronto, Ontario, Canada (n = 50), 22% (n = 22) were employed, 38% (n = 38) were unemployed but medically able to work, 29% (n = 29) were medically disabled, and 10% (n = 10) had retired. The RTW rate for those medically able to work was 37% (22/60), and it was identical at each center (n = 11). Only Canadian lung transplant recipients (36%, 4/11) secured new jobs, whereas all Colorado lung transplant recipients returned to their previous employment (100%, 11/11). A stepwise discriminant analysis revealed that (1) pretransplantation employment, (2) a diagnosis of emphysema, cystic fibrosis, or primary pulmonary hypertension, (3) a self-report of being physically able to work, (4) greater functional improvement as measured by post-lung transplantation percent predicted forced vital capacity, and (5) post-lung transplantation 6-minute walk > 550 m positively influenced RTW. This analysis accurately profiled 82% of the employed and 76% of the unemployed recipients for an overall effectiveness of 79%. The findings of this study are that (1) a 37% employment rate for those physically able was comparable to other types of organ transplant recipients, (2) employment was not determined by the type of lung transplantation procedure (single or bilateral), and (3) social factors remain employment barriers for some recipients, but their absence did not guarantee a better employment rate.

Increasing early success-post lung transplant has been tempered by the long-term development of histologic bronchiolitis obliterans (OB) or of the progressive airway obstruction which is called bronchiolitis obliterans syndrome (BOS). Multiple lines of evidence suggest that OB/BOS is due to an injury directed against the epithelial cells in the airways of the donor lung by the immune system of the recipient. Acute rejection is the strongest risk factor for the subsequent development of this process. Efforts to prevent or minimize acute rejection may reduce the prevalence of OB/BOS. Results of treatment with augmented immunosuppression have been disappointing but the treatment of complicating infections in the allograft can be beneficial. Multicenter studies are needed to assess the efficacy of new immunosuppressive agents in preventing or treating OB/BOS.

Local immunological injury caused by acute lung rejection leads to fibroblast proliferation. Hyaluronate is a product of activated fibroblasts and possibly an indicator of fibroblast proliferation. One hundred thirty-six bronchoalveolar lavage and plasma hyaluronate assays were performed in 57 lung transplant recipients. Pulmonary endothelial cell function was assessed by measuring bronchoalveolar lavage levels of purine nucleoside phosphorylase. Presence of acute cellular rejection was monitored by transbronchial biopsy histologic evaluation and was classified as minimal to mild (acute rejection I, II) and moderate to severe (acute rejection III, IV). Infection was confirmed by bronchoalveolar lavage culture and antibiotic sensitivity. Bronchoalveolar lavage hyaluronate levels in clinically stable recipients were 33.5 +/- 4.69 micrograms/L and were significantly higher than with clinically stable recipients (p = 0.0001), infection (p = 0.008), or mild rejection (p = 0.001). Levels were highest in recipients with diffuse alveolar damage (392.4 +/- 60.6 micrograms/L). Diffuse alveolar damage also resulted in significant elevations of plasma HA as compared with stable recipients (p = 0.001) and mild rejection. We conclude that clinically significant injury to the allograft from rejection or diffuse alveolar damage can be assessed by bronchoalveolar lavage hyaluronate assays and suggest that the source of hyaluronate in these instances are activated fibroblasts.

Microchimerism in lung allograft recipients was studied in the autopsies of nine female recipients of male lung grafts who had survived for more than 1 month after transplantation. Using a Y chromosome-specific probe tissues were studied for the presence of donor cells that had migrated beyond the graft itself. They were quantitated by cell counting to give absolute numbers of cells per organ volume. While donor cells were disseminated throughout the body, their numbers were small. These absolute numbers should be studied in a larger group of recipients to determine if they correlate with prognosis and the development of bronchiolitis obliterans.

Bronchiolitis obliterans, defined histologically or clinically, is the most significant long-term cause of morbidity and mortality after lung transplantation. It shares many pathogenetic features with chronic allograft dysfunction that can occur in bone marrow, liver, heart, and kidney recipients. Lessons learned in the prevention and management of this disorder in lung recipients therefore should have application to the analogous process that develops in other organ allograft recipients. Because the lung is exposed to the external environment, it can be sampled repeatedly by techniques like bronchoalveolar lavage and transbronchial lung biopsy with little or no long-term adverse consequence to the allograft. Excellent pulmonary function tests also are available with which to assess the functional capacity of the allograft and to correlate with the results from immunologic testing. For these reasons, this disorder in lung recipients could serve as a model to determine the pathogenesis and treatment of the analogous disorder that may develop in other major organ recipients. Because this disorder most likely is immunologic in origin, advances in transplant immunology that create tolerance between the donor and recipient as well as efforts to prevent CMV infection and airway ischemic injury likely will be effective preventive measures. Although augmented immunosuppression appears to be of some benefit in treating bronchiolitis obliterans, it is far from optimal and new or better use of current immunosuppressive medications is warranted. Because the number of recipients at any one center is too few to critically assess the efficacy and safety of different immunosuppressive regimens, it is likely that collaboration between transplant centers will be necessary for success to be achieved.

Objective: The experience accrued at the University of Pittsburgh between March 1982 and December 1992 in the various forms of lung transplantation, including heart-lung, double lung, and single lung, is discussed., Summary Background Data: Heart-lung (n = 97) was the most commonly performed operation followed by double lung (n = 80) and single lung (n = 68). Major indications included primary pulmonary hypertension (n = 76), obstructive lung disease (n = 57), Eisenmenger's syndrome (n = 42), cystic fibrosis (n = 32), and retransplantation (n = 13). Since May 1991, 115 procedures have been performed and heart-lung transplantation has decreased from 61% to 15% of the cases with a corresponding doubling in double lung from 24% to 43% and single lung from 15% to 42%., Results: The 1-, 2-, and 5-year survival rates in all 232 recipients were 61%, 55%, and 44%, respectively. The actuarial survival rate was significantly better for those 107 recent recipients compared to the 125 early recipients (70% vs. 61%). Overall, the 63 single (70%) and 74 double (65%) lung procedures were more successful than heart-lung transplantation (53%). Recently, however, lung transplantation has been associated with an improvement in the survival rate from 48% to 72%. The survival rate has also improved from 53% to 77% for single lung transplant recipients. The causes of death in 106 recipients included infection (n = 40), early allograft dysfunction (n = 23), obliterative bronchiolitis (n = 13), and inoperative bleeding (n = 10). Poor outcomes also included technical problems (n = 6), lymphoma (n = 4), acute rejection (n = 3), diaphragmatic paralysis (n = 2), multisystem organ failure (n = 2), stroke (n = 2), liver failure (n = 1), and airway dehiscence (n = 1)., Conclusions: The long-term outlook for lung transplant recipients has improved. There appears to be significant conservation of organs with single lung and double lung transplantation, finding greater acceptance for diseases once exclusively treated by heart-lung transplantation alone. The improved long-term outlook will be dependent upon better treatment for chronic rejection of the airways that histologically is defined by obliterative bronchiolitis.

A clinically applicable, standardized method for assessing functional results after lung transplantation is required to evaluate factors that may affect long-term outcome, to permit comparison of results from different centers, and to evaluate results of clinical trials. An ad hoc working group was established under the auspices of the International Society for Heart and Lung Transplantation for the purpose of developing such a clinically applicable system. Chronic allograft dysfunction is often associated with pathologic findings of obliterative bronchiolitis, the cause of which has not been defined. Physiologically, such dysfunction is associated with obstructive airways disease. The group concluded that the forced expiratory volume in 1 second was the most reliable and consistent indicator of graft dysfunction, excluding other identifiable causes. The term bronchiolitis obliterans syndrome was adopted to describe such dysfunction, recognizing that there may or may not be pathologic evidence of bronchiolitis obliterans present. Four stages of bronchiolitis obliterans syndrome were defined, each with two subcategories to indicate whether pathologic evidence of obliterative bronchiolitis had been identified. This working formulation will require reappraisal in the future to reassess its practical application and to make such adjustments as may seem appropriate.

Between February 1990 and December 1991, 69 patients who survived for a minimum of 5 days after single-lung (27), double-lung (32), or heart-lung transplantation (10) were studied to learn the incidence and severity of acute rejection and the possible effects of various immunosuppressive protocols on this rejection. Acute rejection was less common (2.1 versus 3.1 episodes/patient) after transplantation in those 30 candidates who received rabbit antithymocyte globulin for the first 5 postoperative days versus the 28 who were maintained on cyclosporine, azathioprine, and prednisone alone (p < 0.05), but no patient escaped at least one episode. Patients given cyclosporine received more 3-day courses of methylprednisolone (p < 0.02) than those given rabbit antithymocyte globulin (2.5 versus 1.7 courses). Although no disadvantage in terms of infectious morbidity was noted in the rabbit antithymocyte globulin group, no obvious intermediate advantage was noted in survival (85% at 12 months) or grade of rejection or airway flows. The most common histopathologic grades were mild (A2) and moderate (A3); the average grade was A2.3. FK 506 was tested in 11 patients, and early results are promising relative to low early and likely fewer late episodes of rejection. No differences were noted in the likelihood of rejection for any procedures.

Previous reports have described an association between cytomegalovirus infection and increased donor-specific alloreactivity of bronchoalveolar lavage (BAL) lymphocytes in transplanted lungs and a higher risk of bronchiolitis obliterans due to chronic rejection. We have postulated that during infection, intragraft CMV-specific lymphocytes are activated and release lymphokines that augment cellular rejection. This study deals with an analysis of CMV antigen induced proliferation of 28 BAL lymphocyte and 27 peripheral blood lymphocytes samples from 17 lung transplant patients with or without CMV infection. Kinetic studies of lymphocyte proliferation have shown that CMV infection of the lung allograft is associated with an accelerated response of BAL lymphocytes but not PBL, following in vitro exposure to CMV antigen. These findings indicate an accumulation of primed CMV-specific lymphocytes within the lung allograft during CMV infection. Evidence has also been obtained that primed CMV-specific lymphocytes may persist for months in BAL. We conclude that the CMV antigen induced proliferation assay is useful for studies of CMV infection in transplant patients.

Because infection and rejection are the principal complications of any transplant procedure and because the alveolar macrophage is crucial to the defense of the lung from infection and may play a role in lung allograft rejection, we have begun to assess functions of this cell that are thought to be important in lung defense from infection and in transplant immunity. Antimicrobial functions include chemotaxis, which is a mechanism for recruiting macrophages to sites of inflammation and phagocytosis, and intracellular killing of microorganisms. As an accessory cell, the alveolar macrophage is necessary for an effective immune response to develop against either microorganisms or transplantation antigens. Our results indicate that the chemotactic, phagocytic but not the killing capability of alveolar macrophages from lung recipients is impaired. Alveolar macrophages and blood monocytes from lung recipients are also significantly impaired in their support for mitogen and antigen presentation to lymphocytes. Thus, the generation of an effective immune response to a microorganism may be impaired. Alveolar macrophages from lung recipients, however, function as well as those from normal subjects in stimulating lymphocyte proliferation in response to donor antigens (primed lymphocyte test) or unrelated allogeneic antigens (mixed lymphocyte reaction), while their respective blood monocytes function poorly in this regard. Our conclusions are that the antimicrobial functions of the alveolar macrophages are impaired after lung transplantation and this may be one mechanism to explain the unusual susceptibility of the lung allograft to infection. Those functions related to transplant immunity, however, are preserved and indicate that the alveolar macrophage may play a role in allograft rejection.