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Ann Thorac Surg 1999;67:187-193
© 1999 The Society of Thoracic Surgeons
a Thoracic Surgical, Pediatric Surgical, and Pulmonary and Critical Care Units, and Lung Transplant Program, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA
Address reprint requests to Dr Wain, Massachusetts General Hospital, Blake 1570, Boston, MA 02114
e-mail: wain.john{at}mgh.harvard.edu
Presented at the Thirty-third Annual Meeting of The Society of Thoracic Surgeons, San Diego, CA, Feb 3–5, 1997.
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Abstract |
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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 in-hospital 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.
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Introduction |
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TopAbstractIntroductionMaterial and methodsResultsCommentReferences |
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Although the efficacy of OKT3 in controlling episodes of AR in lung allografts has been demonstrated, its use as 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].
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Material and methods |
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TopAbstractIntroductionMaterial and methodsResultsCommentReferences |
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1-antitrypsin deficiency in 5, lymphangioleiomyomatosis in 2, idiopathic pulmonary fibrosis in 3, desquamative interstitial pneumentis in 3, 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 43 ± 10 years (range, 18–58 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 CMV-negative 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 enzyme-linked immunosorbent assay of bronchoalveolar lavage fluid or nasal washings [13].
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Results |
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TopAbstractIntroductionMaterial and methodsResultsCommentReferences |
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Administration of OKT3 resulted in mild alterations in cardiopulmonary variables that could be readily managed in the postoperative intensive care unit (Fig 1). 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 249 ± 151 to 207 ± 141 mm Hg within 6 hours and then returned to baseline by 12 hours. Patients also developed an increase in core temperature from 36.1 ± 1.7°F to 37.9 ± 0.9°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.
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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).
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Postoperative fungal infections occurred in 8 patients. 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 6.4 ± 3 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).
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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 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.
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Comment |
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TopAbstractIntroductionMaterial and methodsResultsCommentReferences |
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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 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].
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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.
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References |
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TopAbstractIntroductionMaterial and methodsResultsCommentReferences |
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This article has been cited by other articles:
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  J. L. Taylor and S. M. Palmer Critical Care Perspective on Immunotherapy in Lung Transplantation J Intensive Care Med, December 1, 2006; 21(6): 327 - 344. [Abstract] [PDF]
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