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Ann Thorac Surg 1999;68:2279-2283
© 1999 The Society of Thoracic Surgeons

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Original Articles

Comparison of outcomes between living donor and cadaveric lung transplantation in children

^a Division of Cardiothoracic Surgery, Childrens Hospital Los Angeles, University of Southern California School of Medicine, Los Angeles, California, USA
^b Division of Pediatric Pulmonology, Childrens Hospital Los Angeles, University of Southern California School of Medicine, Los Angeles, California, USA
^c Division of Cardiology, Childrens Hospital Los Angeles, University of Southern California School of Medicine, Los Angeles, California, USA
^d Division of Anatomic Pathology, Childrens Hospital Los Angeles, University of Southern California School of Medicine, Los Angeles, California, USA

Address reprint requests to Dr Starnes, Division of Cardiothoracic Surgery, Childrens Hospital Los Angeles, 4650 Sunset Blvd, Mailstop #66, Los Angeles, CA 90027
e-mail: vstarnes{at}chla.usc.edu

Presented at the Thirty-fifth Annual Meeting of The Society of Thoracic Surgeons, San Antonio, TX, Jan 25–27, 1999.

	Abstract

Top Abstract Introduction Material and methods Results Comment References

 
Background. Long-term survival in lung transplant is limited by bronchiolitis obliterans (BOS). We compared outcomes in pediatric living donor bilateral lobar (LL) vs cadaveric lung transplant (CL).

Methods. Children were studied who had LL or CL with at least 1 year follow-up. Data collected included acute rejection episodes, pulmonary function tests (PFT), BOS, and survival. Mean age was 13.36 ± 3.16 years in LL and 12.00 ± 4.19 years in CL patients (p = 0.37, ns).

Results. There was no difference in rejection (p = 0.41, ns). CL had rejection earlier (2.48 ± 3.84 months) than LL (13.60 ± 10.74 months; p = 0.02). There was no difference in 12 month PFT. But at 24 months, LL had greater forced expiratory volume in 1 second (FEV₁) (p = 0.001) and FEF_25–75% (p = 0.01) than CL. BOS was found in 0/14 LL vs 9/11 (82%) CL after 1 year (p = 0.04). After 2 years, 0/8 LL and 6/7 (86%) CL had BOS (p < 0.05). LL had 85% survival vs 79% for CL at 12 months. At 24 months, LL survival was 77% vs 67% for CL.

Conclusions. Pediatric LL had less BOS and better pulmonary function than CL. As BOS is a determinant of long-term outcome, we believe LL is the preferred lung transplant method for children.

	Introduction

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Living donor lobar transplantation was introduced in 1993 as a response to the shortage of cadaveric lung donors [1]. This was particularly evident in the pediatric population. The initial experience was positive, with morbidity and mortality equal to that of conventional cadaveric lung transplantation. However, this procedure was considered only for those individuals thought to be too critical to wait for a cadaveric lung transplant. As experience was accrued, particularly in children, the results were not only equal but superior to that of cadaveric lung transplants [2]. Because of these results, living donor lobar transplantation in children is now an alternative to cadaveric lung transplantation.

Survival and quality of life after lung transplantation is determined primarily by the absence of bronchiolitis obliterans syndrome (BOS). Thought to be a form of chronic rejection, therapy for this lethal complication is ineffective. Different forms of antirejection therapy have not been successful in arresting the progression of this disease once it is established. Children have been more susceptible to BOS and their rate of progression is rapid. The incidence of BOS has reached 50% to 75% by 2 years in most lung transplant programs [3]. Due to their predilection for BOS, children have been considered a high-risk group for lung transplantation, and outcomes have been inferior to adults. Therefore, we and other investigators have viewed bronchiolitis obliterans as a major deterrent to lung transplantation in children. In this report, we will review the outcomes of pediatric cadaveric versus living lobar lung transplants. In particular, we will examine the incidence of BOS in 2 comparable groups of children.

	Material and methods

Top Abstract Introduction Material and methods Results Comment References

 
The study population consisted of pediatric patients who received living donor bilateral lobar (LL) transplantation at Childrens Hospital Los Angeles from 1993 through 1998. All children who underwent LL surgery were also listed for cadaveric organs. However, their disease severity and progression led us and their referring physicians to believe that they would not survive to receive cadaveric lung transplantation. Inclusion criteria included no documentation of medication noncompliance, clinical follow-up for at least 1 year, and the ability to perform pulmonary function testing. This information was compared to children who received cadaveric lung (CL) transplantation in the same institution during the same time period and who met the same inclusion criteria.

All patients (study and control) received standard triple immunosuppression therapy (cyclosporine/tacrolimus, prednisone, azathioprine/mycophenolate mofetil) without (monoclonal or polyclonal) induction therapy. The dose of cyclosporine was adjusted to achieve a whole blood trough level (by fluorescence polarization immunoassay) of 250 to 300 ng/cc. When tacrolimus was used, the trough levels (by microparticle enzyme immunoassay) were kept between 10 and 20 ng/cc. Mycophenolate mofetil was adjusted to maintain a white blood cell count of 5,000 to 12,000 cells/mm³. Corticosteroids were initially administered as 10 to 15 mg/kg and then tapered to achieve a prednisone dose of 0.5 mg/kg/day by postoperative day 30. The long-term prednisone maintenance dose was 0.1 to 0.2 mg/kg/day.

Data collected included demographic information, incidence of acute cellular rejection, incidence of bronchiolitis obliterans syndrome (BOS), incidence of posttransplant lymphoproliferative disease (PTLD), pulmonary function tests (FEV₁, FEF_25–75%, vital capacity, oxygen saturation), exercise stress test, cardiac catheterization, quality of life assessment, and survival/mortality. Acute cellular rejection was determined by transbronchial biopsy that was interpreted by the same pathologist [using the International Society for Heart and Lung Transplantation (ISHLT) grading]. The diagnosis of bronchiolitis obliterans syndrome was based on clinical findings [3, 4] or by lung tissue sample. Lymphoproliferative disease was confirmed by biopsy of suspected lesions. Pulmonary function testing was recorded as percent predicted based upon patient gender and height. A modified Bruce protocol (treadmill) was used to obtain data at maximal exercise on 10 LL and 6 CL patients. Breathing reserve was defined as the ratio of peak minute ventilation to the maximum voluntary ventilation. Cardiac catheterization was performed in 5 patients who had undergone LL procedures. Measurement of right atrial, right ventricular, and pulmonary artery pressures as well as cardiac output and pulmonary vascular resistance were calculated. Quality of life was assessed by the same transplant social worker using a structured interview technique. Results were compared between the groups using unpaired Student’s t test and Fisher’s exact test. Mortality rates were determined by Kaplan–Meier survival analysis. Results are reported as mean and standard deviation. Comparisons between the groups were considered significantly different at p less than 0.05 (two-tail).

	Results

Top Abstract Introduction Material and methods Results Comment References

 
A total of 28 children who could perform pulmonary function tests received lung transplants during the study period. Three of these patients had documented repeated episodes of medication noncompliance and were excluded from analysis. Fourteen patients (6 males:8 females; mean age 13.36 ± 3.16 years) who underwent LL procedure met the inclusion criteria at 1 year posttransplantation. Ten had cystic fibrosis and 4 had primary pulmonary hypertension. Eleven patients (5 males:6 females; mean age 12.00 ± 4.19 years; p = 0.37, ns) who underwent CL surgery met the inclusion criteria 1 year after transplantation. There were 4 patients with cystic fibrosis, 3 with primary pulmonary hypertension, 3 with congenital heart disease, and 1 with pulmonary arterio-venous malformation. At 2 years posttransplant surgery, 8 LL and 7 CL patients were studied.

Seven out of 14 LL patients (50%) had 12 episodes of acute rejection (1.71 episodes/patient) which was not significantly different compared to 24 episodes that occurred in 8 out of 11 CL patients (73%; 2.18 episodes/patient; p = 0.41, ns). But the LL children had less severe grades of rejection (maximum stage A2) as compared to CL (maximum stage A4). The similar incidence of rejection between the LL and CL groups with less severe rejection in the LL recipients has been noted in the adult population [5]. However, the first episode of rejection for LL children (13.60 ± 10.74 months) occurred much later than the first rejection episode for children who received CL procedures (2.48 ± 3.84 months; p = 0.02). Several studies have reported that acute rejection predisposes the patient to the development of bronchiolitis obliterans [6–9]. The fact that CL patients had episodes of acute cellular rejection significantly earlier than LL recipients would increase the risk that BOS would develop in those who received CL transplantation.

Clinical evidence of BOS [3, 4, 10] was noted in 0 of 14 LL patients but in 9 of 11 (82%) CL recipients 1 year after lung transplant (p < 0.04). By 2 years posttransplantation, 0 of 8 LL and 6 of 7 CL (86%) patients had been diagnosed with BOS (p < 0.05). Hence, none of the LL patients who were compliant with their medications have been diagnosed with BOS.

There were no cases of lymphoproliferative disease in pediatric LL recipients. Three CL patients were diagnosed with PTLD: Two had lymphoma found on biopsy of their lung lesions/masses and 1 had a small bowel lesion. These cases of lymphoproliferative disease responded to reduction in immunosuppression alone.

Sustained deterioration in expiratory flow rates is one of the earliest signs of BOS onset in lung transplant patients. One year after transplant surgery, there was no significant difference in vital capacity, FEV₁, FEF_25–75%, and oxygen saturation between LL and CL children (Table 1). However, at 2 years posttransplant, LL recipients had significantly better vital capacity (Fig 1), FEV₁ (Fig 2), and FEF_25–75% (Fig 3) as compared to children who underwent CL procedures (Table 2). These data demonstrate that pediatric LL patients have significantly better preserved pulmonary function than children who underwent CL surgery.

View larger version (18K): [in this window] [in a new window]   Fig 1. Comparison of 12- and 24-month vital capacity. (LL = living donor bilateral lobar transplantation; CL = cadaveric whole lung transplantation.)

View larger version (16K): [in this window] [in a new window]   Fig 2. Comparison of 12- and 24-month FEV1. (LL = living donor bilateral lobar transplantation; CL = cadaveric whole lung transplantation.)

View larger version (16K): [in this window] [in a new window]   Fig 3. Comparison of 12- and 24-month FEF25–75%. (LL = living donor bilateral lobar transplantation; CL = cadaveric whole lung transplantation.)

Except for one CL recipient, all pediatric lung transplant patients returned to school within 1 year after transplantation. Both LL and CL patients felt that they had made the right decision to have lung transplantation. All children studied reported that they enjoyed greater freedom and activity tolerance than prior to their surgery. As importantly, their body image and self-esteem markedly improved after transplant. They reported improved interactions with peers and a "sense of belonging" with friends. They perceived fewer differences between themselves and their friends when they returned to school after transplant. Social competency was improved as they felt more outgoing in social situations and felt good about themselves. All participated in recreational and social activities (eg, team sports or school newspaper) [14].

Survival analysis at 1 year revealed an 85% survival for LL recipients as compared to 79% for CL patients (Fig 4). Two years after transplantation, LL patients had 77% survival and CL patients had 67% survival. This compares very favorably with other published pediatric lung transplant outcome data (65% at 1 year and 69% at 2 years) [10] as well as the ISHLT pediatric registry outcomes (78% at 1 year and 59% at 2 years) [15].

View larger version (15K): [in this window] [in a new window]   Fig 4. Survival data for pediatric living donor and cadaveric lung transplantation. (LL = living donor bilateral lobar transplantation; ISHLT = International Society for Heart and Lung Transplantation.)

	Comment

Top Abstract Introduction Material and methods Results Comment References

Pulmonary spirometry was performed in the 2 comparable groups of LL and CL transplants. These 2 groups were transplanted during the same period, by the same surgical team, for similar indications, and using the same immunosuppression protocols. The FEV₁, FEF_25–75%, and vital capacity were similar for both groups in the first year after transplantation. However, these values were significantly better in the second year after transplantation for LL recipients (Figs 1–3). Further investigation over the 2-year period revealed a decline in these parameters for the CL group while there was a plateau for the LL group values. The irreversible deterioration in pulmonary function is the sine qua non of bronchiolitis obliterans. As noted during the first year after transplantation, 9 of 11 (82%) of the cadaveric lung transplant group developed BOS versus 0/14 in the living donor lobar transplant group. By the second year, 6 of 7 (86%) of the cadaveric group had developed BOS versus 0/8 of the living donor lobar patients (p < 0.05). The difference in BOS incidence between these 2 groups can be speculated. The occurrence of acute rejection appeared earlier (2.48 versus 13.6 months; (p < 0.02) and was more severe in the cadaveric group as compared to the living donor lobar group. The frequency and severity of rejection has been correlated with BOS [6, 8, 9]. The LL group seem to have had a better clinical outcome due to the milder rejection that responded to pulse steroids. As has been previously reported by our group, the degree of antigenic matches or mismatches do not explain these differences in BOS incidence [16]. The explanation of these differences await further investigation.

Successful long-term outcome of lung transplantation is dependent upon the absence of bronchiolitis obliterans syndrome [3, 17, 18]. In view of our findings that pediatric LL recipients have a significantly lower incidence of bronchiolitis obliterans syndrome and have better preservation of pulmonary function, we conclude that living donor bilateral lobar transplantation should be the preferred method of lung transplantation in children whenever possible.

	Acknowledgments

 
The authors gratefully acknowledge the assistance of Rosemary Allen in the preparation of this manuscript.

	References

Top Abstract Introduction Material and methods Results Comment References

 

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This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Add to Personal Folders Download to citation manager Author home page(s): Vaughn A. Starnes Winfield J. Wells Permission Requests Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Starnes, V. A. Articles by Barr, M. L. Search for Related Content PubMed PubMed Citation Articles by Starnes, V. A. Articles by Barr, M. L.