Induction Immunosuppression for Lung Transplantation With OKT3

Transcription

1 Induction Immunosuppression for Lung Transplantation With OKT3 John C. Wain, MD, Cameron D. Wright, MD, Daniel P. Ryan, MD, Susan L. Zorb, RN, Douglas J. Mathisen, MD, and Leo C. Ginns, MD Thoracic Surgical, Pediatric Surgical, and Pulmonary and Critical Care Units and Lung Transplant Program, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts Background. The use of OKT3, an anti-cd3 monoclonal antibody, for immunosuppressive therapy for lung transplantation has been restricted because of concerns regarding infectious risk and cardiopulmonary instability after its administration. Methods. Fifty-two patients received OKT3 (5 mg/d intravenously for 10 days) for induction of immunosuppressive therapy, along with azathioprine (1.5 mg kg 1 d 1 intravenously) and enteral cyclosporine (12 mg kg 1 d 1 ). Maintenance steroid therapy was begun on postoperative day 8. Prophylactic antifungal therapy (fluconazole or amphotericin B) and ganciclovir was used in all patients. Serial transbronchial biopsy and measurements of pulmonary function were used to assess patients for evidence of infection or rejection. Cytomegalovirus infection was diagnosed by biopsy or the presence of cytomegalovirus antigenemia. Results. The 30-day mortality rate was 4%; the inhospital mortality rate was 8%. Acute graft failure was seen in 6 patients. The median length of intubation was 5 days, and the median hospital stay was 30 days. Systemic and pulmonary artery systolic pressures, cardiac index, and ratio of arterial partial oxygen pressure to fraction of inspired oxygen showed no significant alteration after OKT3 dosage. Gram-negative pulmonary infections were identified in 12 patients. Aspergillus infection was seen in 7 patients. Cytomegalovirus infection in 8 patients responded to ganciclovir and did not affect mortality. Respiratory syncytial viral infection was seen in 7 patients. Acute rejection was never seen during OKT3 administration. No episodes of acute rejection were identified in 14 patients at any time postoperatively. In the remainder, episodes of acute rejection responded to steroid or antithymocyte globulin therapy. At a median length of follow-up of 31 months, freedom from obliterative bronchiolitis was 69% 9% at 36 months. The overall survival rate was 88% 5% at 12 months, 82% 6% at 24 months, and 74% 7% at 36 months after transplantation. Conclusions. OKT3 is a safe and effective agent for induction immunosuppressive therapy in lung transplant recipients that limits the incidence of acute rejection and may decrease the incidence of obliterative bronchiolitis. (Ann Thorac Surg 1999;67:187 93) 1999 by The Society of Thoracic Surgeons OKT3 (Ortho Pharmaceutical Corp, Raritan, NJ) is a murine monoclonal antibody that is reactive with the CD3/T-cell receptor complex present on human T cells [1]. Administration of OKT3 interferes with the generation and function of cytotoxic T cells. It has been demonstrated to be effective in controlling acute rejection (AR) involving renal, hepatic, cardiac, and pancreatic allotransplants [2 6]. When OKT3 has been used as an agent for the induction of immunosuppressive therapy in recipients of these grafts, the incidence and severity of AR is less than that seen with standard immunosuppressive regimens. The use of OKT3, however, has been associated with significant acute side effects, including hypotension and pulmonary edema, and with an increased risk for infection and posttransplantation lymphoproliferative disorders [5, 7]. Although the efficacy of OKT3 in controlling episodes of AR in lung allografts has been demonstrated, its use as Presented at the Thirty-third Annual Meeting of The Society of Thoracic Surgeons, San Diego, CA, Feb 3 5, Address reprint requests to Dr Wain, Massachusetts General Hospital, Blake 1570, Boston, MA ( wain.john@mgh.harvard.edu). an agent for induction of immunosuppressive therapy in lung transplant recipients has been associated with an increase in mortality and in the incidence of infection, particularly with cytomegalovirus (CMV) [8, 9]. However, because the development of obliterative bronchiolitis (OB) is the most significant factor affecting the late survival of lung transplant recipients, and because the risk of OB has been related to recurrent or severe episodes of AR, the possibility that induction immunosuppressive therapy with OKT3 may be a regimen that could affect this outcome remains tantalizing [10, 11]. Material and Methods Patient Population Fifty-two lung transplant recipients undergoing operation at the Massachusetts General Hospital from August 1990 to August 1996 received OKT3 as induction immunosuppressive therapy. Recipient diagnoses included pulmonary parenchymal disease in 31 (chronic obstructive pulmonary disease in 17, 1 -antitrypsin deficiency in 5, lymphangioleiomyomatosis in 2, idiopathic pulmonary fibrosis in 3, desquamative interstitial pneumentis in 3, 1999 by The Society of Thoracic Surgeons /99/$20.00 Published by Elsevier Science Inc PII S (98)

2 188 WAIN ET AL Ann Thorac Surg LUNG TRANSPLANTION WITH OKT3 1999;67: scarceidosis in 1); septic lung disease in 15 (cystic fibrosis in 12, idiopathic bronchiectasis in 3); and pulmonary vascular disease in 6 (primary pulmonary hypertension in 4, Eisenmenger s syndrome in 2). There were 21 male and 31 female recipients, with a mean age ( standard deviation) of years (range, years). Median length of follow-up was 31 months. Survival analysis was performed using the method of Kaplan and Meier [12]. Immunosuppressive Therapy Before implantation of the allograft, recipients received cyclosporine (10 mg/kg enterally), azathioprine (5 mg/kg intravenously [IV]), and methylprednisolone (500 mg IV). Before OKT3 administration, histamine-blocking agents (diphenhydramine [50 mg IV], cimetidine [300 mg IV]) and acetaminophen (650 mg rectally) were given. OKT3 (5 mg IV) was administered within 1 hour of the patient s returning to the postoperative care unit. Subsequent doses were administered daily for 10 days. Efficacy was monitored by assays of peripheral T-cell subsets before OKT3 administration and every third day during the duration of therapy. An absolute CD3 count of less than 50 cells was considered therapeutic. The daily OKT3 dose was increased to 10 mg if incomplete clearing of T cells was identified. Cyclosporine (6 mg/kg twice daily) was continued enterally in the postoperative period, with modification of dosing to achieve a serum level of greater than 300 ng/dl. Typically, a therapeutic level was achieved by the end of the first postoperative week. Intravenous cyclosporine (2 mg/kg every 12 hours) was used only when enteral absorption was inadequate. Methylprednisolone (250 mg) was administered every 8 hours in three doses in the immediate postoperative period to ameliorate the hemodynamic effects of OKT3. No further steroids were administered until postoperative day (POD) 8, when prednisone (1.1 mg kg 1 d 1,or its equivalent) was begun. Steroid dosage was tapered biweekly in 10-mg decrements for the first 4 weeks and then biweekly in 5-mg decrements for the next 6 weeks. Further tapering of steroid dosage in 2.5-mg decrements was continued over the first postoperative year to achieve a daily prednisone dose of 15 mg every other day at the first anniversary of the transplant procedure. Infection Prophylaxis Perioperative antibiotic therapy consisted of vancomycin (500 to 750 mg IV every 8 to 12 hours) for prevention of gram-positive line infections and a regimen tailored to the donor s and recipient s sputum flora. All patients received fluconazole (200 mg IV every day) during the course of OKT3 therapy, with the exception of patients with septic lung disease, who received amphotericin B (25 to 35 mg IV every day to a total dose of 600 to 750 mg). Clotrimazole troches (10 mg four times daily) were begun after completion of parenteral antifungal therapy and were continued throughout the postoperative course. All patients received prophylactic ganciclovir (DHPG) therapy, which consisted of 5 mg/kg IV twice a day for 2 weeks, 5 mg/kg IV each day for 2 weeks, 5 mg/kg every other day for 2 weeks, and 1000 mg orally three times a day for 3 weeks. The doses were reduced by half if creatinine levels were greater than 3 mg/dl. No attempt was made to match donor and recipient CMV status. However, for high-risk patients (CMV donor positive/ recipient negative) CMV hyperimmune globulin (150 mg/kg intravenously) was also administered immediately postoperatively, then once a month for 4 months. All blood transfusions were performed with CMVnegative blood using white blood cell filters. Acyclovir (200 mg orally three times a day) was begun after completion of DHPG therapy. Bactrim (one single-strength tablet every day) was begun during the second postoperative week and was continued throughout the postoperative course. Diagnosis of Rejection and Infection Bronchoscopy for observation, sputum sampling, and biopsy were performed daily while patients were endotracheally intubated and subsequently for clinical symptoms of altered pulmonary function. Surveillance transbronchial biopsy (TBBx) of the allograft was performed on PODs 7, 21, 42, and 84 and at 6, 12, 18, 24, and 36 months postoperatively, followed by annual TBBx thereafter. Acute rejection was treated by either methylprednisolone pulses (500 mg IV for 3 days) or oral prednisone recycling (200 mg orally once each day, reduced by 40 mg daily until achieving a dose 10 mg higher than the dose at which the rejection episode occurred). Routine pulmonary function tests and surveillance blood studies were performed weekly for the first 6 weeks postoperatively, biweekly for the next 6 weeks, and then monthly during the first postoperative year. All outpatients performed daily handheld spirometry measurements at home. Chest radiographs were obtained during follow-up visits, and chest computed tomographic scans were obtained according to a schedule similar to that for TBBx. Cytomegalovirus disease was diagnosed by the presence of cytopathic changes or immunohistochemical reaction in biopsy specimens or by the presence of CMV antigenemia in the peripheral blood. Surveillance CMV antigenemia studies were obtained according to a protocol similar to that for TBBx. Respiratory syncytial virus (RSV) infection was diagnosed by membrane enzymelinked immunosorbent assay of bronchoalveolar lavage fluid or nasal washings [13]. Results Single-lung transplantation was performed in 29 patients, and double-lung transplantation, using a sequential single-lung transplantation technique, was performed in 23 patients. Average ischemic time (mean standard deviation) was minutes for one lung and minutes for the second lung. Cardiopulmonary bypass was required in 10 patients, including all 6 patients with pulmonary vascular disease, 2 patients with cystic fibrosis, and 1 patient with restrictive lung disease. Administration of OKT3 resulted in mild alterations in cardiopulmonary variables that could be readily managed in the postoperative intensive care unit (Fig 1).

3 Ann Thorac Surg WAIN ET AL 1999;67: LUNG TRANSPLANTION WITH OKT3 189 Fig 1. Cardiopulmonary effects of OKT3 administration in lung transplant recipients. In the first 24 hours after OKT3 administration no significant change was identified in systemic systolic blood pressure (A) or cardiac index (B), each expressed as a ratio relative to the predose value. A similar ratio of pulmonary artery (PA) systolic blood pressure (C) demonstrated an increase within 4 hours and then a return to baseline values. The ratio of arterial oxygen pressure to fraction of inspired oxygen (pao 2 /FIO 2 ) (D) declined slightly within 6 hours but subsequently improved. Systemic systolic blood pressure decreased on average less than 2% from baseline, whereas cardiac index increased an average of 6% from baseline during the first 6 hours after the dose. Pulmonary artery systolic pressure rose 13% 6% from baseline within 4 hours and returned to predose levels by 12 hours. The ratio of arterial partial oxygen pressure to fraction of inspired oxygen decreased from to mm Hg within 6 hours and then returned to baseline by 12 hours. Patients also developed an increase in core temperature from F to F within 6 hours. Similar but less pronounced alterations were seen after the second dose of OKT3. No further changes were seen with additional dosages of OKT3 beyond 48 hours. Acute graft failure was seen in 6 patients, leading to death from right ventricular failure in 1 patient. Median length of endotracheal intubation was 5 days (range, 1 to 66 days). Median length of intensive care unit stay was 13 days (range, 4 to 80 days). Median duration of hospital stay was 29.5 days (range, 13 to 228 days). The 30-day operative mortality rate was 4% (2 of 52 patients). One patient died of stroke of unknown causes on POD 16 and 1 of right heart failure on POD 17. No patient died during the course of OKT3 therapy. There were two additional deaths before hospital discharge, for an overall in-hospital mortality rate of 8%. These deaths were due to Aspergillus septicemia on POD 42 in a patient with cystic fibrosis who did not receive perioperative amphotericin B therapy and to mediastinitis on POD 228 in an patient with Eisenmenger s syndrome after a course complicated by gram-negative pneumonia, prolonged respiratory failure, and bronchial stenosis. The overall survival rate was 88% 5% at 1 year, 82% 6% at 2 years, and 74% 7% at 3 years (Fig 2). Bacterial infection, all caused by gram-negative organisms, was identified in 11 patients. Gram-negative pneumonia developed in 10 patients and was due to Pseudomonas aeruginosa in 7, Klebsiella pneumoniae in 2, and Serratia marcescens in 1. Pneumonia developed during the postoperative hospital period in 6 patients, including 5 with pneumonia within the first postoperative week, leading to prolongation of endotracheal intubation. All responded to appropriate antibacterial therapy. The remaining episodes of pneumonia occurred more than 3 weeks postoperatively and also responded to antibiotic therapy. The 3 patients who experienced postoperative bronchial complications all experienced early postoperative pneumonias. One recipient with cystic fibrosis experienced an empyema caused by Pseudomonas cepacia on POD 110 that was managed by drainage and ultimately by muscle transposition and partial thoracoplasty. Postoperative fungal infections occurred in 8 patients. Fig 2. Overall survival after induction immunosuppression with OKT3. Kaplan-Meier analysis of survival for all patients.

4 190 WAIN ET AL Ann Thorac Surg LUNG TRANSPLANTION WITH OKT3 1999;67: Table 1. Cytomegalovirus Status of OKT3 Recipients Donor Recipient No. of Patients Fig 3. Survival of patients according to donor (D) and recipient (R) cytomegalovirus status. Kaplan-Meier analysis of survival for patients with donor negative/recipient positive (D /R ), donor positive/recipient negative (D /R ), and concordant donor/recipient status (D/R-C). No significant difference was identified between them by Wilcoxon analysis (p 0.49). Aspergillus infection was seen in 7 patients. One patient with invasive aspergillosis in the early postoperative period died in the hospital on POD 42. In the remaining 6 patients, Aspergillus infection developed more than 3 months postoperatively. Infection at this time was typically associated with an underlying anatomic abnormality in the lung, such as anastomotic granulation tissue or OB. All patients were successfully treated, usually with amphotericin B (35 mg/day IV to a total dose of 800 to 1,000 mg), including 1 patient with Aspergillus fungemia. Persistence of Aspergillus in the sputum after resolution of the acute infection or the presence of Aspergillus in the sputum of patients with OB was treated with itraconazole (200 to 400 mg/day in divided doses). One patient with Aspergillus infection also manifested Scedosporium apiosperium in bronchial washings that was thought to be due to exposure to soil while gardening and was not responsive to therapy, leading to death. An additional patient developed cryptosporidium infection that responded to systemic therapy with fluconazole. Stratification of patients by donor and recipient CMV status is shown in Table 1. Cytomegalovirus infection was seen in 8 patients: 4 of 15 donor negative/recipient positive, 1 of 17 donor positive/recipient negative, 2 of 11 donor positive/recipient positive, and 1 of 9 donor negative/recipient negative. The latter instance of infection in a donor negative/recipient negative recipient was due to intraoperative blood transfusion without a white blood cell filter. One patient (donor positive/recipient negative) experienced systemic CMV disease during an AR episode treated by augmentation of steroids without prophylactic DHPG therapy. In all other patients, prophylactic DHPG therapy during augmentation of the immunosuppressive regimen was successful in preventing CMV infection. Disease was treated by DHPG therapy and administration of CMV hyperimmune globulin for patients with a recipient-negative status. The average duration of DHPG therapy was weeks, and the average total number of courses of DHPG in these patients, including the perioperative prophylaxis, was two. Success of therapy was determined by elimination of peripheral blood CMV antigenemia or resolution of changes on TBBx. All but 2 patients responded promptly to this regimen. Resistance to DHPG was identified in these 2 patients, and foscarnet therapy was instituted, with a reduction in CMV antigenemia levels. No significant difference was seen in mortality between recipients of concordant or discordant CMV grafts (Fig 3). Respiratory syncytial virus was identified in 7 patients (4 men, 3 women). In 5 patients, RSV was diagnosed during an acute respiratory illness, and in 2 patients it was identified during routine bronchoscopic surveillance. All cases of RSV occurred during the months of November to April. Therapy with aerosolized ribavirin was initiated for all patients and was augmented with IV RSV hyperimmune globulin in 2 patients [14]. Adult respiratory distress syndrome occurred in 1 patient, who died; the remaining 6 survived the episode of acute infection. However, 4 of 6 survivors who did not have previous evidence of airway inflammation or OB developed biopsy evidence of bronchiolitis within 3 weeks of their infection. Two of these patients subsequently died within 10 months of bronchiolitis-related respiratory failure. Only 1 patient developed a posttransplant lymphoproliferative disorder on POD 55. Analysis revealed this disorder to be a monoclonal Epstein-Barr virus related proliferation. The source of the Epstein-Barr virus was in fact the allograft because the recipient was seronegative for Epstein-Barr virus both before and after transplantation. The posttransplant lymphoprofliferative disorder responded to a reduction in immunosuppression and immunoglobulin G therapy. The recipient is alive, with no evidence of disease 30 months after transplantation. Monitoring for AR was performed using clinical variables, TBBx, and radiographic study, in particular, chest computed tomographic scanning. No patient developed AR while receiving OKT3. Fourteen patients who survived beyond 30 days had no evidence of AR at any time during their postoperative course. In the remaining 35 patients, AR was seen at a median of 18 days postoperatively (range, POD 14 to 405) and was usually grade 1 [15]. Of these patients, 18 developed a second episode of AR a median of 140 days postoperatively (range, POD 42 to 405), and 8 developed a third episode of AR a median of 277 days postoperatively (range, POD 120 to 1,080). Rejection episodes at these times were also usually grade 1. Only 2 patients had more than three episodes of AR, and only 3 patients had AR histologically assessed as

5 Ann Thorac Surg WAIN ET AL 1999;67: LUNG TRANSPLANTION WITH OKT3 191 Fig 4. Freedom from obliterative bronchiolitis (O.B.). Kaplan-Meier analysis of freedom from obliterative broncholitis for all patients surviving beyond 60 days (n 49). grade 3. Response to steroid therapy for AR was seen in 34 of 35 patients. Antithymocyte globulin was used for AR in 5 patients (in 2 at the time of the first episode of AR caused by the severity of graft dysfunction, in 3 after a third episode of AR). Antithymocyte globulin therapy resulted in control of all remaining episodes of AR. Chronic rejection of the allograft or OB was assessed by either TBBx or by the clinical criteria of the bronchiolitis obliterans syndrome (BOS) in the 49 patients surviving beyond 60 days [14]. By histologic criteria, OB was identified in 13 patients (26%), inclusive of the 4 patients with post-rsv bronchiolitis. By clinical criteria, BOS was identified in 17 patients (35%) (stage 1 in 8 patients, stage 2 in 4, stage 3 in 5). Freedom from OB was 90% 5% at 12 months, 79% 7% at 24 months, and 69% 9% at 36 months (Fig 4). Chronic rejection was seen in 3 patients in whom no episodes of AR had been previously identified. Stage 2 BOS or greater was usually treated by increased steroid dosage. In 2 patients in whom BOS and histologic OB were seen within 12 months of transplantation, a course of antithymocyte globulin was administered, followed by crossover to a tacrolimus regimen. Comment The administration of OKT3 results in the activation of complement and the release of lymphokines, which have been reported to have profound effects on cardiopulmonary function [3, 5, 7]. In our experience, some mild elevations in pulmonary artery systolic pressure were seen, accompanied by a mild reduction in oxygenation and pyrexia within 6 hours of administration of the first dose. These effects were self-limited and resolved within 12 hours, although they did recur, to a much lesser extent, with the second dose. No further significant changes were seen with repeated doses of OKT3. Although an increase in pulmonary as well as systemic capillary permeability is a secondary effect of OKT3 administration, judicious fluid management combined with the use of positive end-expiratory pressure and pulmonary vasodilators provided adequate control of these phenomena in our patients. The ability to monitor these patients in an intensive care unit setting, allowing prompt therapeutic interventions, most likely contributed to their successful treatment. The subsequent course of the patient in the intensive care unit and the hospital appeared to be determined more by other factors, such as recipient right heart function and the development of invasive infections, than by any initial cardiopulmonary effects of OKT3, as has been reported for lung transplant recipients treated without cytolytic induction therapy [16]. Although all patients received pretreatment with steroids, histamine-blocking agents, and acetaminophen, the significance of these measures in preventing the acute OKT3 response is difficult to assess. The 30-day operative mortality rate (4%) and inpatient mortality rate (8%) and the overall survival of our patients compare favorably to results from other transplant centers [10, 17, 18] (Table 2). Acute mortality from infection in our patients appeared to be eliminated with more aggressive use of prophylactic antimicrobial therapy, particularly for Pseudomonas and Aspergillus. Acute graft failure occurred with a frequency in our patients similar to that reported from centers using noncytolytic induction therapy, suggesting that OKT3 was not directly causal to this problem. In addition, the administration of OKT3 in patients with acute graft dysfunction did not further worsen their cardiopulmonary status. As reported by others, acute graft failure in our patients did not affect overall survival, although it most likely contributed to the death of the recipient who died of right heart failure on POD 16. The consistent incidence of this dysfunction among lung transplant centers, despite a Table 2. Results of Lung Transplant Induction Immunosuppression Regimens Site and Regimen Hospital Mortality Rate (%) Acute Rejection (%) 1-Year Survival Rate (%) 2-Year Survival Rate (%) Incidence of OB (Biopsy) Prevalence of BOS (%) UPgh Cya 7.4 (30day) NA Tacro 6.3 (30day) NA WashU Cya MGH OKT BOS bronchiolitius obliterans syndrome; Cya cyclosporine steroid induction regimen; MGH Massachusetts General Hospital; OB obliterative bronchiolitis; Tacro tacrolimus steroid induction regimen; UPgh University of Pittsburgh (Keenan and coworkers [17]; Washington University School of Medicine (Cooper and colleagues [10], Sundaresan and coworkers [18]).

6 192 WAIN ET AL Ann Thorac Surg LUNG TRANSPLANTION WITH OKT3 1999;67: variety of immunosuppressive and prophylactic antimicrobial regimens, strongly suggests that other factors, possibly related to the preprocurement state of the donor, are involved in the etiology of this problem [10, 16]. Finally, the occurrence of only three bronchial complications in our 52 patients compares favorably to the reported 10% incidence of bronchial complications occurring in patients receiving cyclosporine steroid induction immunosuppressive therapy [10]. Prophylactic therapy with DHPG has been shown to control the incidence of CMV infection in lung transplant recipients receiving standard induction immunosuppressive therapy [11]. The inability to control the incidence of CMV infection in patients receiving induction immunosuppressive therapy with OKT3 was the major reason for avoiding this type of therapy for lung transplant recipients [9]. In our experience, the use of prophylactic DHPG has effectively prevented the development of symptomatic CMV disease in patients receiving OKT3, regardless of donor/recipient CMV status. When patients have developed evidence of CMV disease, manifested either as cytopathic or immunohistochemical changes on TBBx or by elevations in surveillance CMV antigenemia levels, the therapeutic use of DHPG proved successful in eliminating the disease in 6 of 8 patients. In the remaining 2 patients, the failure of DHPG appeared to be the result of CMV resistance to this drug. In these 2 patients, alternative therapy with foscarnet was used with success. The control of CMV infection in lung transplant recipients is particularly pertinent given the reported association between CMV status and mortality [19, 20]. However, in our patients receiving CMV prophylaxis, there was no significant difference in mortality between recipients with CMV concordant and discordant allografts (Fig 3). Finally, because DHPG has additional activity against Epstein-Barr virus, the etiologic agent for most posttransplant lymphoproliferative disorder, the use of this therapy may account for the very low incidence of posttransplant lymphoproliferative disorder in our patients receiving OKT3. Respiratory synctial virus has been identified as a significant pathogen causing pneumonitis in immunocompromised adults as well as neonates [21]. Infection with RSV has been associated with respiratory failure and the development of bronchiolitis in these populations, with a particular predilection for the development of these complications in male subjects [21, 22]. The availability of a membrane enzyme-linked immunosorbent assay to detect RSV in nasal washings and bronchoalveolar lavage fluid allows for rapid detection of this pathogen. Routine surveillance for RSV among our transplant recipients has identified an unexpectedly high incidence of infection. The majority of patients have been symptomatic, with an apparent upper respiratory infection. All patients have received aerosolized ribavirin therapy. Significantly, post-rsv bronchiolitis has been identified in 4 patients (3 men, 1 women) within 3 weeks of initial infection. The potential role of RSV in the pathogenesis of OB-like lesions in lung transplant recipients may need to be reassessed in view of the seasonal nature of this disease and the reported seasonal variation in the incidence of OB [23]. The use of OKT3 for induction of immunosuppressive therapy in lung transplant recipients appears to reduce the incidence and severity of AR compared with published reports using non cytolytic-based induction immunosuppression regimens [11, 17] (Table 2). When AR did occur, the use of high-dose steroids or antithymocyte globulin resulted in reversal of the process. Therefore, the relative inability to use OKT3 as an agent for control of AR in patients who had received it as part of an induction regimen was not a major problem. The anticipated potential for OKT3 for induction of immunosuppressive therapy to achieve allograft tolerance has not been realized for extrapulmonary organ transplant [3 5]. A similar experience seems to be apparent from our patient population. Although the prevalence and severity of BOS in our patients is less than that reported for standard cyclosporine steroid induction regimen at a comparable follow-up interval, freedom from OB in our patients is similar to that reported for lung transplant recipients receiving a tacrolimus steroid induction regimen [17, 18] (Table 2). Although recurrent or severe AR, or both, has been associated with the development of chronic rejection, 3 of our patients who developed histologic OB had no evidence of AR. Symptoms of BOS and histologic evidence of OB were seen in our patients despite the control of the AR process achieved by the use of OKT3 induction therapy, which raises the possibility that in some patients additional factors, such as minor histocompatibility antigens or infectious agents, may be involved in the pathogenesis of this chronic graft dysfunction. Further follow-up will be required to ascertain whether OKT3 induction immunosuppressive therapy offers any clinical or cost-effective advantages with regard to AR or OB compared with noncytolytic induction regimens. References 1. Kung PC, Goldstein G, Reinherz EL, Schlossman SF. Monoclonal antibodies defining distinctive human T-cell surface antigens. Science 1979;206: Cosimi AB, Colvin RB, Burton RC, et al. Use of monoclonal antibodies to T-cell subsets for immunologic monitoring and treatment in recipients of renal allografts. N Engl J Med 1981; 305: Debure A, Chkoff N, Chatenoud L, et al. One-month prophylactic use of OKT3 in cadaver kidney transplant recipients. Transplantation 1988;45: Cosimi AB, Cho SI, Delmonico FL, Kaplan MM, Rohrer RJ, Jenkins RL. A randomized clinical trial comparing OKT3 and steroids for treatment of hepatic allograft rejection. Transplantation 1987;43: Renlund DG, O Connell JB, Gilbert EM, et al. A prospective comparison of murine monoclonal CD-3 (OKT3) antibodybased and equine antithymocyte globulin-based rejection prophylaxis in cardiac transplantation. Transplantation 1989; 47: Stratta RJ, Sollinger HW, D Alessandro AM, Kalayoglu JDP, Belzer FO. OKT3 rescue therapy in pancreas allograft rejection. Diabetes 1989;38(Suppl 1): Abramowicz D, Schandene L, Goldman M, et al. Release of tumor necrosis factor, interleukin-2, and gamma-interferon in serum after injection of OKT3 monoclonal antibody in kidney transplant recipients. Transplantation 1989;46: Shennib H, Massard G, Reynaud M, Noirclerc M. Efficacy of

7 Ann Thorac Surg WAIN ET AL 1999;67: LUNG TRANSPLANTION WITH OKT3 193 OKT3 therapy for acute rejection in isolated lung transplantation. J Heart Lung Transplant 1994;13: Calhoon JH, Nichols L, Davis R, et al. Single lung transplantation: factors in postoperative cytomegalovirus infection. J Thorac Cardiovasc Surg 1992;103: Cooper JD, Patterson GA, Trulock EP, et al. Results of single and bilateral lung transplantation in 131 consecutive recipients. J Thorac Cardiovasc Surg 1994;107: Bando K, Paradis IL, Komatsu K, et al. Analysis of timedependent risks for infection, rejection and death after pulmonary transplantation. J Thorac Cardiovasc Surg 1995;109: Kaplan EL, Meier P. Non-parametric estimation from incomplete observations. J Am Stat Assoc 1958;53: Hughes JH, Mann DR, Hamparian VV. Detection of respiratory synctial virus in clinical specimens by viral culture, direct and indirect immunofluoresence and enzyme immunoassay. J Clin Microbiol 1988;26: Committee on Infectious Diseases. Use of ribavirin in the treatment of respiratory syncytial virus infection. Pediatrics 1993;92: Yousem SA, Berry GJ, Cagle PT, et al. Revision of the 1990 working formulation for the classification of pulmonary allograft rejection: lung rejection study group. J Heart Lung Transplant 1996;15: Sommers KE, Griffith BP, Hardesty RL, Keenan RJ. Early lung allograft function in twin recipients from the same donor: risk factor analysis. Ann Thorac Surg 1996;62: Keenan RJ, Konishi H, Kawai A, et al. Clinical trial of tacrolimus versus cyclosporine in lung transplantation. Ann Thorac Surg 1995;60: Sundaresan S, Trulock EP, Mohanakumar T, et al. Prevalence and outcome of bronchiolitis obliterans syndrome after lung transplantation. Ann Thorac Surg 1995;60: Duncan SR, Paradis IL, Yousem SA, et al. Sequelae of cytomegalovirus pulmonary infections in lung allograft recipients. Am Rev Respir Dis 1992;164: Keenan RJ, Lega ME, Dummer JS, et al. Cytomegalovirus serologic status and postoperative infection correlated with risk of developing chronic rejection after pulmonary transplantation. Transplantation 1991;51: Englund JA, Sullivan CJ, Jordan MD, et al. Respiratory syncytial virus infection in immunocompromised adults. Ann Intern Med 1988;109: Everard ML, Milner AD. The respiratory syncytial virus and its role in acute bronchiolitis. Eur J Pediatr 1992;151: Hohlfeld J, Niedermeyer J, Hamm H, Schafers HJ, Wagner TOF, Fabel H. Seasonal onset of bronchiolitis obliterans syndrome in lung transplant recipients. J Heart Lung Transplant 1996;15: DISCUSSION DR J. KENT TRINKLE (San Antonio, TX): I was just talking to my friend and colleague, Fred Grover. This is a blast from the past. We started using OKT3 about 10 years ago in lung transplants. It is an excellent but dangerous immunosuppressant. The increased incidence of CMV is real! When we first started using OKT3, we had a terrible CMV problem before we recognized it and subsequently have used both ganciclovir (DHPG) and immunoglobulin when we give OKT3. The second thing is that it is nice when you have the initial lysis of lymphocytes and the release of lymphokines if you give that first dose under anesthesia either immediately before or after revascularization when the patient is also intubated. It blunts that first horrible reaction. Another important point is that when you discontinue OKT3 you get a rebound blastogenesis, and if you do not recycle or increase the corticosteroids, there will be an acute rejection a few days after you stop it. So starting the day or two before you discontinue OKT3, go ahead and recycle your steroids. The last point is that if you continue beyond about 10 days, you occasionally will have a hypersensitivity reaction. We recall seeing this on several occasions in patients who would have athetoid movements and become febrile and semicomatose. This is reversible, but absolutely horrible the first time you see it. So we now limit it to 10 days with the initial course. DR WAIN: Yes, I would certainly agree that in terms of the CMV problem, it is real. I think that with adequate DHPG prophylaxis you can prevent the vast majority of that, particularly if OKT3 as an induction agent is used without concomitant steroid therapy. As I pointed out, we did limit our treatments to 10 days, so we were able to avoid some of the later complications of it. Our episodes of acute rejection did occur most commonly within 1 to weeks after discontinuation of the OKT3, perhaps relating to the blastogenesis that you referred to, and patients did respond to steroid pulses at that time. DR JAMES K. KIRKLIN (Birmingham, AL): First, some have clinically observed in heart transplantation that an initial lower dose of OKT3, either 1 or 2.5 mg as an initial dose, and then sequentially increasing it may decrease these hemodynamic effects. Did you ever consider an initial protocol of, say, 2.5 mg? Second, it seems as if your duration of hospital stay is longer than perhaps you would like in this era of cost-containment. Was that influenced by the duration of DHPG therapy intravenously or was the completion of the DHPG given on an outpatient basis? DR WAIN: With regard to your first question, I think we have developed a level of comfort with the hemodynamic changes associated with the OKT3. We have not used a reduction in the initial dose because we have basically been able to ride things out. We have found that keeping patients warm intraoperatively and a little better hydrated than normal greatly limits a lot of the hemodynamic changes that occur in the immediate postoperative period. We have not found that the use of nitric oxide, as an example, has really blunted as much of the hemodynamic effects as we had hoped. It is also unclear to us whether the pretreatment with acetaminophen, steroids, and histamine blockers has any beneficial effect. Certainly if we were greatly concerned, I think reducing the OKT3 dosage would be appropriate. In terms of the length of the hospital stay, I think that clearly does not relate to the DHPG therapy. Most patients receive DHPG on an outpatient basis with an indwelling central line at the present time. The length of hospital stay has more to do, I think, with us not having developed a streamlined process to get patients through more quickly, a protocol we are working on at the present time. DR BERNARD HAUSEN (Melon Park, CA): I enjoyed your presentation. I am a little concerned. If you look at the International Society of Heart and Lung Transplantation (ISHLT) database, the incidence of OB at 3 years, I think, is something like 55% to 65%. That is about what you have as well. So I do not really see the advantage in reducing the incidence of OB with OKT3. DR WAIN: Our freedom from OB at 3 years is 69%. Put another way, our incidence of OB at 3 years is 31%. So it is a little better than the ISHLT data and, in fact, is similar to the results reported with tacrolimus induction immunosuppression.