ACTO CONSTITUCIONAL La república Dominicana es constitucionalmente desde su fundación un Estado libre e independientemente cuyo gobierno es esencialmente civil, republicano, democrático y representativo, y su organización política debe estar fundada en el efectivo ejercicio del sufragio. La celebración de elecciones libre es, pues, el medio más eficaz de consultar la voluntad soberana d
Doi:10.1016/j.healun.2003.10.020Lung Transplantation: A Decade of Experience
Susan D. Moffatt, MD, PhD,a Philippe Demers, MD,a Robert C. Robbins, MD,a Ramona Doyle, MD,bAnn Wienacker, MD,b Noreen Henig, MD,b James Theodore, MD,b Bruce A. Reitz, MD,a andRichard I. Whyte, MDa Background:
Over the past 3 decades, the field of lung transplantation has been refined. However, many barriersexist that limit long-term success. The purpose of this study was to review a single institution’slong-term experience with single and double lung transplantation and to assess the effect ofdifferent immunosuppressive therapies on outcomes.
Lung transplant recipients, both single and double, were reviewed, retrospectively. Patientswere divided into five groups: group I, all lung transplants (n ϭ 127); group II, single lungtransplants (n ϭ 73); group III, double lung transplants (n ϭ 54); group IV, OKT3 inductiontherapy recipients (n ϭ 27); and group V, RATG induction therapy recipients (n ϭ 100). Ratesof survival, rejection, bronchiolitis obliterans syndrome (BOS) and infection were analyzed at 1,3, and 5 years.
There were no significant differences in survival, acute rejection rate, freedom from BOS, norinfection between single and double lung transplant recipients. Induction therapy with RATG(group V) was associated with significantly improved survival and freedom from acute rejection,BOS, and infection when compared to OKT3 induction therapy (group IV).
An earlier impression that RATG is superior to OKT3 induction therapy has borne true in terms ofoverall survival and incidence of BOS, acute rejection and infection rates. Lung transplantation,using RATG induction therapy, remains an important modality for end-stage pulmonary disease.
J Heart Lung Transplant 2005;24:145–51. Copyright 2005 by the International Society for Heartand Lung Transplantation.
Since Cooper and Patterson described successful single morbidity and mortality in the first 5 years after trans- and double lung transplantation in 1986 and 1988, respectively, more than 8,000 lung transplants have Chronic rejection has been reported in up to 50% of been performed in the United During the past three decades, the field of transplantation has improved target of the immune response in chronic rejection is in the areas of organ preservation, immunosuppressive the bronchial epithelium and the disease is manifested therapy, and control of infectious and neoplastic com- histologically as obliterative bronchiolitis (OB). Since OB is difficult to diagnose, a committee sponsored by now accepted as appropriate treatment for end-stage the International Society for Heart and Lung Transplan- tation (ISHLT) proposed a clinical description of OB, One-year survival for lung transplant recipients has termed bronchiolitis obliterans syndrome This risen from 47% in 1988 to 75% in 2001. By comparison, is defined by pulmonary function changes rather than long-term survival is 47% at 5 years and only 20% at 10 histology. BOS encompassed both a decline in pulmo- Acute graft failure and reperfusion injury are the nary function and/or histologic evidence of chronic most common causes of early mortality whereas infec- tion and chronic rejection are the major causes of Currently, there is no consensus as to the best immunosuppressive regimen and in particular the useof induction Induction therapy is the use From the aDepartment of Cardiothoracic Surgery, and bDivision of of an immunosuppressive agent other than that used for Pulmonary and Critical Care Medicine, Stanford University, Stanford, maintenance immunosuppression to attempt tolerance induction in the perioperative period. OKT3 and RATG Submitted June 26, 2003; revised September 10, 2003; accepted are induction agents used in lung as well as heart and Reprint requests: Richard I. Whyte, MD, Department of Cardiothoracic Surgery, CVRB 205, 300 Pasteur Drive, Stanford, CA 94305-5407. Tele- clonal antibody that binds to the CD3/T cell receptor phone: 650-723-6649. Fax: 650-725-3846. E-mail: firstname.lastname@example.org complex and inhibits the generation of cytotoxic T Copyright 2005 by the International Society for Heart and Lung cells. RATG is a polyclonal anti-thymocyte antibody that Transplantation. 1053-2498/05/$–see front matter. doi:10.1016/j.healun.2003.10.020 reduces the number of effector T lymphocytes. Advo- The Journal of Heart and Lung Transplantation Table 1. Ischemic Times for Lung Allografts
the availability of the locally produced RATG. As of December 1993, RATG was routinely used with a dose of 1.5 mg/kg given intravenously on post-transplant days 1, 2, 3, 5, and 7 after pre-medication with diphen- hydramine and acetaminophen. OKT3 (5 mg/kg) was given intravenously on post-transplant days 1 to 5 with Methylprednisolone 500 mg IV was given to all patients immediately before reperfusion. Cyclosporin was startedpostoperatively when hemodynamics and renal function cates of induction therapy believe that it reduces the were stable; azathioprine was initiated in the operating room.
incidence of early acute rejection and the development Maintenance immunosuppression consisted of cyclosporin of BOS; critics argue that the increased risk of infec- (Sandimmune or Neoral) 5 to 10 mg/kg po daily to maintain tion and post transplant lymphoproliferative disorders whole blood levels of approximately 300 ng/ml, azathioprine (Imuran) 2 mg/kg po daily, and prednisone 0.6 mg/kg po This study reviewed a single institution’s long-term experience with single and double lung transplantation.
Furthermore, to better understand the role of induction Long-term Follow-up and Management
therapy and improve patient outcomes, a comparison Surveillance bronchoscopy with transbronchial biopsy of RATG vs OKT3 therapy was undertaken.
was performed at 2, 4, 8, and 12 weeks and then at 6months and 1 year post-transplant. Long-term follow-up MATERIAL AND METHODS
included bronchoscopy every 6 months to 1 year or Patients who underwent single or double lung transplan- when clinically indicated. Pulmonary function tests, a tation at Stanford University between 1989 and 1999 were chest X-ray and arterial blood gases were done at each reviewed retrospectively. Patients who had previously follow up visit or when clinically warranted. Acute received heart-lung transplants or lung transplants (n ϭ 4) rejection was defined as any episode of grade II rejec- were excluded from the analysis. Patients who did not tion diagnosed on transbronchial biopsy. Rejection was receive adult (Ͼ16 years old) donor allografts were ex- treated with methylprednisolone 1 g intravenously daily cluded (n ϭ 4). The remaining 127 patients were analyzed for 3 days and an increase in the prednisone dose.
according to type of transplant (double vs single) and type Persistent rejection was treated with an additional of induction therapy (OKT3 vs RATG) with respect to course of steroids followed by RATG, OKT3 or total survival, freedom from rejection, freedom from BOS and Patients were divided into group I (all lung trans- Infection Prophylaxis
plants [n ϭ 127]), group II (single lung transplants [n ϭ Infection was defined as any infectious event that 73]), group III (double lung transplants [n ϭ 54]), required treatment, either as an inpatient or outpatient.
group IV (OKT3 induction therapy [n ϭ 27]), and Infections could have been viral, bacterial, fungal or group V (RATG induction therapy [n ϭ 100]).
As of December 1993, all CMV-mismatched donor– Lung Procurement and Implantation
recipient pairs received intravenous Ganciclovir, 5 mg/kg Donor lung preservation consisted of 500 g of Prosta- IV twice a day for 14 days and 6 mg/kg IV daily for 20 days glandin E that was given directly into the pulmonary for a total of 34 days, Cytovene (oral Ganciclovir), 1,000 artery followed by an infusion of 4 liters of ice cold mg per os three times a day for 6 weeks and Cytogam (IgG Eurocollins solution. The lung block was placed in iced immunoglobulin), 150 mg/kg 72 hours post-transplant, saline for transport. All allograft ischemic times were 100 mg/kg weeks 2, 4, 6, 8 post-transplant, and 50 mg/kg weeks 12 and 16. Before the introduction of Cytovene and Allograft implantation was performed without cardio- Cytogam in 1993, all CMV-mismatched recipients received pulmonary bypass for the majority of the single lung transplants whereas double lung transplants were per- Pneumocystis carinii pneumonia prophylaxis con- formed with cardiopulmonary bypass support in the sisted of trimethoprim/sulfamethoxazole DS twice daily, Monday, Wednesday and Friday. Aspergillus pro-phylaxis consisted of aerosolized Amphotericin B 20 mg Immunosuppression Regimem
twice daily while hospitalized and itraconazole 200 mg Between January 1989 and November 1993, patients per os every morning and 100 mg per os every night for received RATG or OKT3 induction therapy based on The Journal of Heart and Lung Transplantation Table 2. Indications for Lung Transplantation
COPD, chronic obstructive pulmonary disease.
Definition of BOS
immunosuppressive regimens among the two groups (p Bronchiolitis obliterans syndrome is defined by the ISHLT as a greater than 20% decline in FEV and/or Survival Rates Higher for Recipients of RATG Induction
Individual charts were reviewed and a diagnosis of BOSwas based on either decline in lung function that was The overall survival rate of all lung transplant recipients demonstrated on two separate visits at least 2 weeks (Group I) was 83%, 67%, and 47% at 1, 3, and 5 years, apart and/or histologic evidence of obliterative bronchi- respectively. The survival rates for the single lung transplant recipients (Group II) were 81%, 69%, and45%, respectively, whereas those for double lung recip- Data Collection and Statistics
ients (Group III) were 88%, 66%, and 55%, respectively, Patient data were systematically collected pre- and at 1, 3, and 5 years with no significant difference post-transplant by the Stanford transplant nurse coordi- nators. Actuarial life-table data were calculated by the Recipients treated with OKT3 induction therapy Cutler-Ederer method. Time-related event-free rates (group IV) had survival rates of 71%, 50%, and 29% at 1, were reported from actuarial estimates as the mean Ϯ 3, and 5 years, respectively, while those who received standard error. Comparison between actuarial curves RATG (group V) had survival rates of 86%, 71%, and was made by the Gehan method. Comparison between 53%, respectively. These results were statistically differ- group demographics was made using the Student’s t-test. Significance for all comparisons was defined as p There were a total of 69 deaths among the 127 recipients. The major causes of death among all lungtransplant recipients were BOS (n ϭ 35, 51%), infection (n ϭ 21, 30%), and malignancy (n ϭ 3, 5%) as outlined Transplant Patient Demographics
in Type of transplant (single vs double) nor The mean age at time of transplantation was 34 Ϯ 10 type of induction therapy (RATG vs OKT3) influenced years and 74 (58%) were women. The most common the cause of death (p Ͻ 0.005).
indications for lung transplantation were emphysema/COPD (26%), cystic fibrosis (24%), and idiopathic pul- Acute Rejection Rates Higher Among Lung Transplant
monary fibrosis (14%) as detailed in Among the Recipients That Received OKT3 Induction Therapy
single lung transplant recipients, 56 received RATG and The overall freedom from acute rejection for all lung 17 received OKT3. Among the double lung transplant transplant recipients (group I) was 57%, 53%, and 53% recipients, 44 received RATG and 10 received OKT3.
at 1, 3, and 5 years, respectively. The corresponding This represented a statistically equivalent distribution of rates for single and double lung transplant recipients Table 3. Lung Transplant Survival Data
The Journal of Heart and Lung Transplantation Figure 1. Survival rates among OKT3 (group IV) and RATG (group V)
Figure 2. Freedom from acute rejection, at 1 year, in lung transplant
treated lung transplant recipients. There was significantly improved recipients treated with OKT3 induction therapy (group IV) or RATG survival among those transplant recipients who received RATG induc- induction therapy (group V). Freedom from rejection was significantly tion therapy compared with those who received OKT3 induction less when lung transplant recipients were treated with OKT3 induction therapy (p Ͻ 0.005). OKT3 ϭ OKT3 induction therapy group (group IV); therapy. (p Ͻ 0.005) OKT3 ϭ OKT3 induction therapy group (group IV); RATG ϭ RATG induction therapy group (group V).
RATG ϭ RATG induction therapy group (group V).
were 54%, 49%, and 49% compared with 58%, 56%, and56% at 1, 3, and 5 years, respectively; these did not respectively. The infection rate among the single lung recipients (group II) was 79%, 91%, and 91%, and for The freedom from rejection among the transplant double lung transplants recipients (group III) 64% at 1, recipients that received RATG was significantly higher 3, and 5 years, respectively. These infection rates were than compared to recipients of OKT3 induction therapy (64%, 62%, and 62% vs 26%, 13%, and 13%, at 1, 3, and The cytomegalovirus (CMV) infection rate among all 5 years, respectively; p Ͻ 0.005; lung transplant recipients (group I) was 54%, 65%, and70% at 1, 3, and 5 years. The CMV infection rate among Incidence of BOS Significantly Higher Among Transplant
the single lung recipients (group II) was 72%, 84%, and Recipients Receiving OKT3 Induction Therapy
88%; CMV infection rate for the double lung transplant A total of 54 patients of BOS were diagnosed: 22 recipients (group III) was 57%, 64%, and 64%, at 1, 3, (41%) by histology and 32 (59%) by clinical deterio- and 5 years, respectively. These CMV infection rates were not found to be significantly different.
BOS (group I) was 84%, 64%, and 40% at 1, 3, and 5 The rate of infectious events requiring treatment, years, respectively. For single lung transplant recipi- was significantly higher among the OKT3 treated ents (group II), freedom from BOS was 86%, 63%, and recipients (group IV 89%, 100%, and 100% at 1, 3, and 34%, and for double lung transplant recipients (group 5 years, respectively) compared with the RATG III), it was 81%, 66%, and 49%, at 1, 3, and 5 years, treated recipients (66%, 80%, and 80% at 1, 3, and 5 respectively. These rates of BOS were not signifi- years, respectively; p Ͻ 0.005; group V). The rate of CMV infection was also significantly higher among Lung transplant patients who received OKT3 (group the OKT3 treated recipients (group IV, 74%, 87%, and IV) had significantly less freedom from BOS (77%, 47%, 87%) compared with RATG treated recipients (group and 20% at 1, 3, and 5 years, respectively) compared with V, 61%, 71%, and 73%) at 1, 3, and 5 years respec- those who received RATG (group V; 89%, 72%, and 49% at 1, 3, and 5 years, respectively; p Ͻ 0.005; DISCUSSION
Infection Rates Higher Among Lung Transplant Recipients
This 10-year review of lung transplant experience re- Receiving OKT3 Induction Therapy
veals overall survival rates similar to the United Net- The infection rate among lung transplant recipients work of Organ Sharing (UNOS) and ISHLT databases (group I) was 72%, 84%, and 84% at 1, 3, and 5 years, that report 1, 3, and 5 year survival rates of 75%, 58%, Table 4. Cause of Death in Lung Transplant Recipients
The Journal of Heart and Lung Transplantation further compared the use of OKT3 vs RATGinduction therapy in lung transplant recipients andfound no difference in survival. These varying dataprompted us to compare our recipient outcomes usingthe different induction regimens and present the resultsof this comparison.
Acute rejection typically occurs in the first 3 to 6 months after transplantation with most recipientssuffering at least one episode.The rejection ratesamong our single and double transplant patients were Figure 3. Freedom from BOS in lung transplant recipients treated
similar and in keeping with those of other centers with OKT3 induction therapy (group IV) vs those treated with RATG Rejection rates were, however, significantly less in induction therapy (group V), at 5 years. There was a significant the RATG treated group compared to the OKT3 difference in the incidence of BOS between these OKT3 and RATG treated group. This difference between treatment treatment groups (p Ͻ 0.005). BOS ϭ bronchiolitis obliterans groups had been pre-viously perceived and prompted syndrome; OKT3 ϭ OKT3 induction therapy group (group IV); RATG changing to RATG induction therapy in 1993. Wain et ϭ RATG induction therapy group (group V).
aldemonstrated that OKT3 induction preventedearly rejection and reduced the overall incidence of acute rejection episodes. Likewise, Palmer et al plantation as well as our demographics appear to be in using RATG, demonstrated that the number of pa- tients experiencing biopsy proven rejection was sig- Induction therapy is an attempt at inducing a “toler- nificantly reduced compared to the patients without induction therapy. These findings differ with Brock et not use induction therapy, however, report survival who, in a 4-year prospective controlled clinical outcomes as high as 80% at 2 Differing opinions trial comparing OKT3, ATG, and dacluzimab, re- and outcomes using induction therapy exist in the vealed no significant differences in episodes of acute literature. Wain et investigated the role of OKT3 in a prospective trial whereby OKT3 induction therapy Our comparison demonstrated that the incidence was given for 10 days followed by cyclosporin-based of pulmonary infection was significantly greater maintenance therapy. The overall survival of lung trans- among the OKT3 treated patients compared with the plant recipients was similar to those patients not receiv- RATG treated recipients. Brock et asimilarly found ing OKT3 but acute rejection was Wiebe et that OKT3 resulted in significantly more infections.
investigated ATG induction therapy in both lung and Our rates of infection may relate to the fact that heart-lung transplant recipients and found no survival OKT3 treated patients were part of our early experi- benefit compared with no induction therapy. Palmer et ence when CMV prophylaxis was not optimized.
Since 1994 a rigorous regimen of CMV prophylaxishas been successfully implemented including oraland IV Ganciclovir and immune gamma globulinAlternatively, the high incidence of infections amongOKT3 recipients may reflect additional immunosup-pression required for treatment of acute rejectionepisodes in this group.
In this 10-year review the incidence of BOS was found to be equal among the single and double lungtransplant recipients but overall higher than that re-ported by the ISHLT registry (60% vs 50% at 5 years, Figure 4. Freedom from CMV infection, at 1 year, among the lung
respectively) which may reflect a long study period and transplant recipients that received OKT3 induction therapy (group IV) an aggressive examination of transplant data on our and RATG induction therapy (group V). There was a significant part. Our data reveals that the OKT3-treated recipients difference among the immunosuppressive regimen groups in that the had a higher incidence of BOS compared to those OKT3 treated (group IV) recipients had a significantly higher incidence having received RATG. In addition, OKT3-treated recip- of CMV infection events when compared with the recipients treated ients suffered more acute rejection and CMV infection with RATG (p Ͻ 0.005). CMV ϭ cytomegalovirus; OKT3 ϭ OKT3induction therapy group (group IV); RATG ϭ RATG induction therapy episodes as compared to those treated with RATG.
Although not causal, the association of multiple acute The Journal of Heart and Lung Transplantation rejection and CMV infection episodes resulting in BOS, the UNOS/ISHLT International Registry for thoracic organ as reported by others, are supported by our results transplantation. Clin Transpl 2000;31– 44.
Induction therapy and outcome data are difficult to 4. DeMeo DL, Ginns LC. Clinical status of lung transplanta- interpret due to variation in drug administration in tion. Transplantation 2001;72:1713–24.
5. Hertz MI, Taylor DO, Trulock EP, Boucek MM, Mohacsi terms of dose, formulation, duration of therapy and era PJ, Edwards LB, Keck BM. The registry of the Interna- of administered. Induction immunosuppression has tra- tional Society for Heart and Lung Transplantation: nine- ditionally been used at our institution but clearly OKT3 teenth official report–2002. J Heart Lung Transplant 2002; was administered early on in our experience when organ preservation, operative technique, and postoper- 6. Taylor DO. Immunosuppressive therapies after heart ative care varied from current standards. The decision transplantation: best, better and beyond. Curr Opin Car- to administer OKT3 or RATG was based on personal pre-ference and drug availability, ultimately resulting in 7. Reichenspurner H, Girgis RE, Robbins RC, et al. Obliter- a small number of OKT3-treated patients. Early in our ative bronchiolitis after lung and heart-lung transplanta- experience, RATG was not commercially available and tion. Ann Thorac Surg 1995;60:1845–53.
8. Estenne M, Maurer JR, Boehler A, et al. Bronchiolitis was in fact “home brewed” for recipients in a local obliterans syndrome 2001: an update of the diagnostic laboratory. Barlow et alpreviously investigated out- criteria. J Heart Lung Transplant 2002;21:297–310.
comes among lung and heart-lung recipients who re- 9. Brock MV, Borja MC, Ferber L, et al. Induction therapy in ceived OKT3 or RATG early in our experience and lung transplantation: a prospective controlled clinical trial found there to be a survival and outcome advantage for comparing OKT3, antithymocyte globulin, and dacli- RATG transplant recipients. Our study, incorporating a zumab. J Heart Lung Transplant 2001;20:1282–90.
decade of experience, further supports and emphasizes 10. Barr ML. Current status of heart and lung transplantation.
The limitations of this review, therefore, include it 11. Wain JC, Wright CD, Ryan DP, et al. Induction immuno- being retrospective whereby patients could not be suppression for lung transplantation with OKT3. AnnThorac Surg 1999;67:187–93.
randomized to RATG, OKT3 or no induction therapy.
12. Wiebe K, Harringer W, Wahlers T. ATG induction therapy CMV prophylaxis has changed over time. The effect and the incidence of bronchiolitis obliterans after lung cardiopulmonary bypass on outcomes was not studied transplantation: does it make a difference? Trans Proc because practically all single lung transplants were performed without cardiopulmonary bypass whereas 13. Kriett JM, Smith CM, Hayden AM, et al. Lung transplanta- the majority of double lung recipients had cardiopul- tion without the use of antilymphocyte antibody prepa- monary support. Donor and recipient age criteria were rations. J Heart Lung Transplant 1993;12:915–22.
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Lecture Notes on Kant by D.H.Th. Vollenhoven Institute for Christian Studies, Fall 1977, Monism Character: Position of psyche with regard to soma is otherwise than with dualism. It is not that of inner to outer, but of higher to lower. Meanwhile, neither one or the other says anything concerning the place of psyche and soma with respect to the origin. On this point there are a number of differe