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Ann Thorac Surg 2010;90:1110-1115. doi:10.1016/j.athoracsur.2010.05.074
© 2010 The Society of Thoracic Surgeons
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Right arrow Lung - transplantation

Original Articles: General Thoracic

Induction Therapy With Antithymocyte Globulin Before Reperfusion

Samuel B. Goldfarb, MDa,*, J. William Gaynor, MDb, Stephanie Fuller, MDb, James Kreindler, MDa, Lisa M. Montenegro, MDc, Francis Fynn-Thompson, MDd, Gary Visner, DOe

a Division of Pulmonary Medicine, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania
b Division of Cardiothoracic Surgery, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania
c Division of Cardiothoracic Anesthesiology, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania
d Department of Cardiac Surgery, Children's Hospital Boston, Boston, Massachusetts
e Department of Pulmonary Medicine, Children's Hospital Boston, Boston, Massachusetts

Accepted for publication May 25, 2010.

* Address correspondence to Dr Goldfarb, Division of Pulmonary Medicine, 11th Flr Colket Bldg, The Children's Hospital of Philadelphia, 34th St and Civic Center Blvd, Philadelphia, PA 19104 (Email: goldfarb{at}email.chop.edu).

Presented at the Forty-sixth Annual Meeting of The Society of Thoracic Surgeons, Fort Lauderdale, FL, Jan 25–27, 2010.


   Abstract
Top
 Abstract
Introduction
 Material and Methods
 Results
 Comment
 Discussion
 References
 
Background: The use of induction immunosuppressive agents in pediatric lung transplantation is not universal. The rationale of induction therapy is to use the strongest immunosuppressive drugs at the time when the risk of acute cellular rejection (ACR) is highest. The timing of induction is not universal. We hypothesize that early treatment with antilymphocyte globulin (ATG) prior to reperfusion of the first donor lung will decrease the incidence of ACR.

Methods: The initial dose of ATG was given during the operative procedure when the recipient was on cardiopulmonary bypass after removal of the recipient lungs and prior to implantation. Patients received additional doses daily for four days. All children were monitored for ACR during the first 6 months posttransplant with transbronchial biopsies at defined intervals (weeks-months) and when clinically indicated. Presence of ACR was defined by International Society for Heart & Lung Transplantation guidelines.

Results: Recipients from two pediatric centers received ATG based on this protocol. A total of 18 patients were treated with this protocol, and the follow-up period was 6 to 45 months. A total of 63 flexible bronchoscopies with transbronchial biopsies were performed during the first 6 months. A single episode of ACR (≥ grade A2) was identified in this patient population for an incidence of 5.2% ACR grade A2 or above in this patient population.

Conclusions: Induction therapy with ATG prior to donor lung reperfusion is associated with a low incident of ACR during the first 6 months posttransplant in our patient cohort. Long-term follow-up is needed to ascertain the full effect of this treatment protocol.


   Introduction
Top
 Abstract
 Introduction
Material and Methods
 Results
 Comment
 Discussion
 References
 
Lung transplantation is reserved for patients with end-stage progressive lung disease or life-threatening pulmonary vascular disease for which no other medical or surgical options exist. Long-term survival after lung transplantation is limited by the onset of acute and chronic rejection leading to graft dysfunction. Chronic rejection in the form of bronchiolitis obliterans (BO) is the leading cause of graft dysfunction and ultimate graft loss leading to mortality in lung transplant recipients [1]. Attempts to decrease graft dysfunction and ultimate graft failure have focused on reducing the incidence of acute cellular rejection (ACR) by employing induction drug therapy. The reported incidence of ACR in patients during the first year after lung transplantation ranges from 18% to 50% with induction therapy, while it is more than 50% to 55% without induction [2–4].

Risk factors for ACR include human leukocyte antigen mismatching, community acquired viral infection, and the immunosuppressive regimen [5]. Most importantly, ACR is an independent risk factor for later development of BO [6–8]. Moreover, the association of a single episode of ACR grade 2A was recently shown to significantly increase the risk for BO in the pediatric population [9]. Therefore, prevention of ACR is a critical component of posttransplant management. One approach to minimize ACR is the use of induction therapy. The rationale for induction therapy is to use more potent immunosuppressive reagents at the time when the risk of ACR is highest in the first few weeks after transplantation. The use of induction immunosuppressive agents in pediatric lung transplantation is not universal. Forty percent of the pediatric centers surveyed reported using induction therapy in the postoperative period. The use of interleukin (IL)-2 receptor antagonists is greater than polyclonal antilymphocyte globulin (ATG) based on International Society for Heart & Lung Transplantation data [1]. Initiation of induction therapy during the peritransplant period varies from institution to institution with the majority beginning in the immediate posttransplant period [2, 10–12].

Few studies report the use of induction therapy preoperatively or intraoperatively. We hypothesize that early treatment with ATG prior to reperfusion of the first donor lung will decrease the incidence of ACR. In this study we evaluated our data in which ATG was given intraoperatively prior to implantation of the donor lung. We observed a low incidence of ACR in our pediatric lung transplant population suggesting that intraoperative dosing of ATG is more efficacious in preventing early ACR after lung transplantation.


   Material and Methods
Top
 Abstract
 Introduction
 Material and Methods
Results
 Comment
 Discussion
 References
 
Recipients
This is a retrospective analysis of all patients undergoing bilateral lung transplant at The Children's Hospital of Philadelphia between June 2006 and September 2009 and Children's Hospital Boston between January 2008 and September 2009. Approval from both institutional review boards was obtained. Informed consent was obtained from all subjects. All eligible patients who received induction therapy with rabbit antithymocyte globulin (rATG) were included. Patients who were determined to have a preexisting immune abnormality or higher risk for infectious complications were not given induction therapy.

The rATG was the induction therapy used in all patients with an initial dose of rATG (1.5 mg/kg/dose maximum 150 g) given during the operative procedure while the recipient was on cardiopulmonary bypass after removal of the recipient lung(s) and prior to implantation and reperfusion. All patients were placed on cardiopulmonary bypass as the preferred technique of the surgical teams at both institutions. Patients received additional doses daily for 4 days with dosing adjusted based on a sliding scale as reported by Krasinskas and colleagues [13] of absolute peripheral CD3+ T-lymphocytes counts. Dose adjustments were made to maintain a CD3+ count less than 100 cells/µL. Patients also received methylprednisolone (30 mg/kg) with a maximum of 1,000 mg when on cardiopulmonary bypass.

Maintenance immunosuppression therapy posttransplant included tacrolimus (trough levels were maintained between 10 and 15 ng/mL), mycophenolate or azathoprine (if mycophenolate was not tolerated), and steroids (methylprednisolone given at 2 mg/kg prior to ATG and followed by prednisone starting post-ATG at 0.5 mg/kg or maximum of 20 to 25 mg). All patients received prophylaxis antibiotics based on respiratory cultures prior to transplant. Antifungal medications and cytomegalovirus (CMV) prophylaxis were used based on donor and recipient CMV positive or CMV negative status or when clinically indicated. The CMV prophylaxis was as follows: When donor was positive and recipient was negative, recipient received intravenous ganciclovir with transition to oral valganciclovir in addition patients received cytogam; for donor CMV negative and recipient CMV positive or donor CMV positive recipient CMV negative intravenous ganciclovir with transition to oral valganciclovir was used; when both donor and recipient were CMV negative no CMV prophylaxis was used. All patients received Pneumocystis carinii prophylaxis.

Monitoring for ACR during the first 6 months posttransplant was performed by transbronchial biopsies performed at 4 weeks, 3 months, 6 months, and when clinically indicated. Presence of ACR was a histologic diagnosis based on the presence of perivascular and interstitial mononuclear cell infiltrates. The grading system was based on the International Society for Heart & Lung Transplantation revised consensus statement and graded as A0 (none) to A4 (severe); grade A2 acute rejection and above was treated with augmented immunosuppression [14, 15]. Pathologists from each center confirm the diagnosis and if it is unclear results were reviewed at a consensus meeting by several pathologists.

Descriptive data are presented. The survival estimates were calculated using the Kaplan-Meier method.


   Results
Top
 Abstract
 Introduction
 Material and Methods
 Results
Comment
 Discussion
 References
 
Twenty-two patients received bilateral lung transplants during the study period. Eleven patients out of 13 transplanted at The Children's Hospital of Philadelphia received ATG. Two were excluded from receiving induction therapy; one patient had previously received a bone marrow transplant and did not have full reconstitution of all cell lines and was already on immunosuppressive medications while the second patient was 19 months old and at the time our institutional protocol did not use induction therapy given the greater risk for infection in this age group. At Children's Hospital Boston, 7 of 9 patients received induction therapy with ATG. Of the two patients excluded one had received alemtuzumab several months prior to transplantation and still had low absolute lymphocyte counts and, while the second patient excluded was colonized with Burkholderia dolosa, induction therapy was thought to increase the risk for overwhelming infection at the time of transplant. A total of 18 patients received rATG based on this protocol. The median age at transplantation was 13 years (range, 18 months to 19 years). Females represented 56% (10 of 18) of our patient population. Prior to transplant 44% (8 of 18) required some form of ventilator support either noninvasive ventilation or mechanical ventilation (Table 1). The median follow-up was 15.2 (17.2) months (range, 6 to 45 months). Indications for lung transplant were the following: cystic fibrosis (n = 8); pulmonary hypertension (n = 5); bronchiolitis obliterans (n = 3); and other (n = 3).


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  		Table 1 Patient Demographics and Diagnosis
 
All eligible patients received one dose of rATG of 1.5 mg/kg when on cardiopulmonary bypass after removal of the recipient lungs and prior to implantation and reperfusion of the donor lung. All patients demonstrated a reduction in their peripheral CD3 counts to average levels below 100 cells/µL during the five days of therapy. The CD3 counts increased and began to normalize by day 10 posttransplant (Fig 1).


Figure 1
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  		Fig 1. Peripheral CD3+ counts show an appropriate response to ATG therapy in the first 14 day postoperative period.

 
There were no perioperative deaths and no deaths during the first 6 months after transplantation. There have been two late deaths; one patient died at 11 months from multiorgan failure and diffuse alveolar hemorrhage, it was unclear the etiology, and no infectious pathogens were cultured. The second patient died at 35 months posttransplant, several months after becoming nonadherent and stopping all immunosuppression medications. The overall survival rate at one year, of patients who received induction therapy with rATG, at 12 and 24 months was 91.7% (11 of 12) and 73.3% at 36 months (Fig 2).


Figure 2
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  		Fig 2. Kaplan-Meier survival curve survival estimates are 91.7% at 12 and 24 months and 73.3% at 36 months.

 
A total of 65 flexible bronchoscopies with transbronchial biopsies were performed during the first 6 months for an average of 3.6 bronchoscopies with transbronchial biopsies per patient. Fifty-six procedures were performed as per standard protocol and nine procedures were performed based on clinical indications to rule out ACR. All pathologic samples met criteria for evaluation of ACR. During this time period there was a single episode (5.2% of patients) ACR grade A2 or above. The incidence of observed ACR grade A2 or above as determined by tissue biopsy was 1.53%. This patient was treated for ACR with pulse steroids. No other patients in this cohort were treated during the first 6 months with pulse steroids for either biopsy negative or clinically diagnosed ACR.

The only early (within 30 days posttransplant) infectious complication was a single urinary tract infection. There were no surgical wound infections and no early airway complications. Late complications (30 days to 6 months) included airway complications in two patients requiring temporary airway stenting. There were two late bacterial infections: one line infection and one urinary tract infection; neither was life threatening and both responded to antibiotic therapy. There were five episodes of respiratory viral infections and one CMV pneumonitis infections (Table 2).


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  		Table 2 Complications
 

   Comment
Top
 Abstract
 Introduction
 Material and Methods
 Results
 Comment
Discussion
 References
 
In this cohort, initiation of induction therapy with rATG prior to reperfusion of the donor lungs is associated with a low incidence of ACR. There was no adverse effect of induction therapy on either early survival or the incidence of infectious complications. There is inadequate follow-up to determine if there is a beneficial effect in terms of overall survival and chronic graft dysfunction.

Results from this study report a lower incidence of ACR than previously reported in the pediatric population. Visner and colleagues [16] found an incidence of ACR in a mixed cohort with not all patients receiving induction therapy, and those that did received it posttransplant, in the first year at 24% from surveillance biopsies while the rate was even higher when biopsies were performed based on clinical indication. Brock and colleagues [2] reported in their cohort, in which they compared three different induction therapy agents, a high incidence of ACR with at least 50% of patients with one episode of rejection by the fifth month posttransplantation. No difference was observed among ATG, OKT3, and daclizumab in the incidence of rejection. Initiation of induction therapy was not standardized; only daclizumab being given intraoperatively, and ATG and OKT3 being given within 24 hours of transplant. This occurred in an adult cohort and its incidence of ACR was quite high in comparison with our pediatric cohort. Hartwig and colleagues, in a prospective randomized trial [11], initially observed a low incidence of 5% of ACR in the first 6 months in the induction therapy group treated with ATG; however, in long-term follow-up there was no overall difference in ACR between the ATG group and the control group.

The majority of induction therapy protocols in lung transplantation give the induction agent after completion of the surgery [4, 6, 17]. There are several studies in solid organ transplantation whose protocols specifically use induction therapy prior to or at the time of organ reperfusion transplant [10, 18–20]. In a study comparing two ATG protocols in renal transplantation Agha and colleagues [19] reported that the timing of ATG therapy along with an increased ATG dose allowed for shorter duration of therapy, with greater absolute T-cell suppression in the first 30 days posttransplant. While rejection and graft survival rates were the same in both groups early induction therapy allowed for a shorter treatment period with a more sustained T cell suppression. Similarly, Starzl and colleagues [20] reported results from their trial where all solid organ (which included kidney, liver, pancreas, or intestinal) transplants performed in this cohort received induction therapy prior to transplantation and in all organ groups there was an overall improved graft survival rate. Table 3 reviews additional studies performed in solid organ transplantation which analyze the use of induction therapy and its timing. Our protocol of induction therapy at the time of reperfusion is similar to protocols used in other solid organ transplantation.


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  		Table 3 Selected Review of Studies Comparing the Use of Induction Therapy and Timing of Doses in Solid Organ Transplants
 
Understanding ATG's properties and effects might shed light in understanding our results. The effects of ATG are robust and ATG has a half-life of 30 days [21]. Long-term suppression of T cells often persists beyond one year [18, 22]. Antilymphocyte globulin has many properties which include blocking T cell activation and antigen recognition at the time of transplant. In addition to T cell depletion it induces apoptosis of B cell lineages and interferes with dendritic cell, regulatory T cell, and natural killer cell functions [23].

In addition to T cell depletion ATG has an effect on leukocyte adhesion at the time of reperfusion. Antilymphocyte globulin is thought to modulate key functional molecules that mediate leukocyte adhesion to endothelium and alter the extent of allograft rejection and ischemia reperfusion injury [24, 25]. Conversely ATG's affect on regulatory T cells is thought to be of promotion or expansion and not suppression. In experimental models preliminary data reveal that ATG may promote expansion of Treg cells, which is thought to induce allograft tolerance [26, 27].

This paper describes the experience at two institution of a modified antilymphocytic induction therapy prior to implantation of the donor lung in 18 pediatric patients. Induction therapy consisting of ATG prior to donor lung reperfusion is associated with a low incidence of ACR during the first 6 months posttransplant in our patient cohort.

While early mortality is low, the impact of prereperfusion induction therapy on long-term graft function and survival is not known. Randomized clinical trials with longer follow-up are needed to determine if induction therapy prior to donor lung reperfusion improves long-term outcomes.


   Discussion
Top
 Abstract
 Introduction
 Material and Methods
 Results
 Comment
 Discussion
References
 
DR SETH D. FORCE (Atlanta, GA): I have a few questions. I have three questions actually.

The first question is, when you compared this to your historical cohort who did not get induction therapy, or not at least in this way, did you see any increase in infections in these patients?

The second question is, did you have to stop—I think you gave it for four days, correct?

DR GOLDFARB: Correct.

DR FORCE: Did you have to stop the therapy for severe graft dysfunction or other infection in any of these patients?

And then my third is why do you think it makes a difference giving it at reperfusion versus the next morning?

DR GOLDFARB: So in regards to the first question, we don't have a cohort prior to that where I could compare infection rates, and therefore we were unable to compare them. However, there is literature from pediatric centers Danziger-Isakov et al who have combined their data to show the infection rate particularly of CMV (cytomegalovirus) in the pediatric population. In this study there was comparison between groups that received some form of induction therapy and those that did not.

And the biggest risks for infection seem to be younger age since they have had less opportunity for exposure to more viral pathogens. The second question was?

DR FORCE: The second question was, did you have to stop the therapy in any of these patients at any time during their four days?

DR GOLDFARB: No. Well, we might have either decreased a dose or missed a dose based on CD3 levels, but in general we continued it. The majority completed a five day course.

And last, why do I think this is different than any other one? I don't know if I thought it before we started, but I think that there's some evidence to show that giving the ATG (antilymphocyte globulin) or some form of induction therapy prior to transplant will decrease the number of T cells and it turns the hosts response to the newly transplanted organ. And what I tried to allude to in that one slide was that not only does ATG effect T cells numbers and function, which there is thought to be a dose-dependent response, there's also some interaction earlier in the vasculature. So when you have the reperfusion injury, it could be theorized that there's less of an inflammatory response, and I think that might, this might also modify the host's response to a new organ. The other thing is it also affects antigen-presenting cells, in essence how the body recognizes the new graft. And I think several hours might make a significant difference in the process of inducing tolerance to the new organ. There are many protocols that initiate induction therapy 12 to 24 hours after transplant.

DR CHRISTINE L. LAU (Charlottesville, VA): I have two questions for you as well. I very much enjoyed the talk.

Have you thought about measuring T-reg cells since you think they're going to be increased? That's my first question.

The second question is, in the adult population, we give an IL-2 [interleukin 2] receptor antagonist with one advantage being that we can hold the tacrolimus for a few days if necessary.

Do you find that you're starting the tacrolimus in the children population after the ATG?

And then the third question, have you considered changing from ATG to an IL-2 because of the ease of giving it?

DR GOLDFARB: Right. So remind me of your first question.

DR LAU: Have you measured T-reg cells or have you thought about it?

DR GOLDFARB: No. T-reg cells we haven't measured, but I'm actually interested in doing that. At the University of Pennsylvania Wayne Hancock has been studying T-regs among other cell types. I hope to collaborate with him in determining how we can incorporate testing levels in transplant recipients; which ones do well and looking at it.

And he has some preliminary data that he's done already with liver transplant and decreasing immunosuppression. What we'd like to be able to find out is how to enhance T-regs, I guess, overall activity and then be able to adjust our immunosuppression based on that.

DR LAU: Whether or not to use a tacro?

DR GOLDFARB: Oh, yes. So we do hold the tacrolimus, and we're able to start that usually on the third or fourth day. If we get into trouble, occasionally we use IV (intravenous) cyclosporine, but it does allow you to back away from using it in the early postoperative stage.

And then the last question?

DR LAU: Have you thought about switching?

DR GOLDFARB: We've had pretty good response to ATG. I don't think we would change our protocol. However we are always reevaluating our results and looking at other center's experiences.

I know that, for example, St. Louis uses an IL-2 receptor, and I think maybe that might be a comparison group for us.


   References
Top
 Abstract
 Introduction
 Material and Methods
 Results
 Comment
 Discussion
 References
 

  1. Aurora P, Edwards LB, Christie JD, et al. Registry of the International Society for Heart and Lung Transplantation: twelfth official pediatric lung and heart/lung transplantation report-2009 J Heart Lung Transplant 2009;28:1023-1030.[Medline]
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  3. Knoop C, Haverich A, Fischer S. Immunosuppressive therapy after human lung transplantation Eur Respir J 2004;23:159-171.[Abstract/Free Full Text]
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  26. Lopez M, Clarkson MR, Albin M, Sayegh MH, Najafian N. A novel mechanism of action for anti-thymocyte globulin: induction of CD4+CD25+Foxp3+ regulatory T cells J Am Soc Nephrol 2006;17:2844-2853.[Abstract/Free Full Text]
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