Abstract
Lung transplantation is a well-established treatment for advanced lung diseases. In children, the diseases that most commonly lead to the need for a transplantation are cystic fibrosis, pulmonary hypertension, and bronchiolitis. However, the number of pediatric lung transplantations being performed is low compared with the number of transplants performed in the adult age group. The objective of this study was to demonstrate our experience with pediatric lung transplants over a 10-year period in a program initially designed for adults.
Lung Transplantation; Pediatrics; Cystic Fibrosis; Bronchiectasis; Bronchiolitis
INTRODUCTION
Lung transplantation (LTx) is now a well-established therapy for treating various chronic lung
diseases that lead to severe respiratory failure. LTx has improved significantly since it began in
1963 with James Hardy (11. Hardy JD. Lung Homotransplantation in Man. JAMA. 1963;186(12):1065-74,
http://dx.doi.org/10.1001/jama.1963.63710120001010.
http://dx.doi.org/10.1001/jama.1963.6371...
). An increasing number of studies
have focused on studying the indications, techniques, immunosuppressive drugs, and criteria for
donation. The first pediatric LTx occurred in 1987 in a 16-year-old boy with familial pulmonary
fibrosis (22. Mendeloff EN. The history of pediatric heart and lung transplantation. Pediatr
Transplant. 2002;6(4):270-9, http://dx.doi.org/10.1034/j.1399-3046.2002.00217.x.
http://dx.doi.org/10.1034/j.1399-3046.20...
).
The annual number of pediatric lung transplants performed is significantly lower than that of
adult transplant surgeries performed each year. According to a 2013 report from the International
Society of Heart and Lung Transplantation, from 1986 to June 2012, in patients younger than 18
years, 1875 lung transplants and 667 double heart and lung transplantations were reported (33. Benden C, Edwards LB, Kucheryavaya AY, Christie JD, Dipchand AI, Dobbels F, et
al. The Registry of the International Society for Heart and Lung Transplantation: sixteenth official
pediatric lung and heart-lung transplantation report—2013; focus theme: age. J Heart
Lung Transplant. Elsevier; 2013;32(10):989-97,
http://dx.doi.org/10.1016/j.healun.2013.08.008.
http://dx.doi.org/10.1016/j.healun.2013....
), whereas there were 3640 transplanted adults in 2011 (44. Yusen RD, Christie JD, Edwards LB, Kucheryavaya AY, Benden C, Dipchand AI, et al.
The Registry of the International Society for Heart and Lung Transplantation: thirtieth adult lung
and heart-lung transplant report—2013; focus theme: age. J Heart Lung Transplant.
2013;32(10):965-78, http://dx.doi.org/10.1016/j.healun.2013.08.007.
http://dx.doi.org/10.1016/j.healun.2013....
).
The most common indication for LTx in patients up to 18 years old is cystic fibrosis (33. Benden C, Edwards LB, Kucheryavaya AY, Christie JD, Dipchand AI, Dobbels F, et
al. The Registry of the International Society for Heart and Lung Transplantation: sixteenth official
pediatric lung and heart-lung transplantation report—2013; focus theme: age. J Heart
Lung Transplant. Elsevier; 2013;32(10):989-97,
http://dx.doi.org/10.1016/j.healun.2013.08.008.
http://dx.doi.org/10.1016/j.healun.2013....
), a fact that is also demonstrated in this study. Other
indications for LTx include bronchiolitis obliterans, bronchiectasis, pulmonary arterial
hypertension, idiopathic fibrosis, interstitial lung diseases, and surfactant protein abnormalities
(55. Huddleston CB. Pediatric lung transplantation. Curr Treat Options Cardiovasc.
Med. 2011;13(1):68-78, http://dx.doi.org/10.1007/s11936-010-0105-6.
http://dx.doi.org/10.1007/s11936-010-010...
).
The aim of this study was to describe the pediatric lung transplantation experiences at the Heart Institute (InCor) of Faculdade de Medicina da Universidade de São Paulo.
PATIENTS AND METHODS
A retrospective analysis of the medical records of patients undergoing lung transplantation at the Heart Institute (Incor) of Hospital das Clínicas da Faculdade de Medicina de São Paulo was performed for the period from January 2003 to October 2013.
RESULTS
From February 2003 to October 2013, 192 lung transplants were performed at our institution (11 patients 18 years old and younger). The recipient distribution by age and diagnosis is shown in Figure 1.
All 11 pediatric patients underwent bilateral sequential LTx; two patients required cardiopulmonary bypass during surgery. To date, the longest surviving pediatric transplant patient underwent surgery 5 years ago when he was 11 years old.
Two patients suffered immediate postoperative death less than one month post transplantation. The first patient, whose initial diagnosis was idiopathic pulmonary arterial hypertension, developed primary graft dysfunction and died on the 4th postoperative day. This patient was six years old and required cardiopulmonary bypass. The second patient, a 17-year-old adolescent diagnosed with bronchiolitis obliterans associated with secondary pulmonary hypertension, also underwent cardiopulmonary bypass; the patient developed refractory hemodynamic instability and died three days post-surgery.
One patient with an initial diagnosis of bronchiectasis died three years after undergoing transplantation for chronic graft dysfunction with clinical restrictive syndrome. A 16-year-old patient with an initial diagnosis of post-infectious bronchiolitis obliterans syndrome later developed obliterative bronchiolitis and underwent retransplantation three years after the initial procedure.
In our institution, induction therapy is performed with 10 mg/kg intravenous methylprednisolone, with basiliximab in the case of initial suppurative disease. The maintenance immunosuppression combines corticosteroids (prednisone), calcineurin inhibitor (cyclosporine or tacrolimus), and a cellular activation inhibitor (azathioprine or mycophenolate sodium).
The complications related to the immunosuppressive regimen were infection (in the majority of cases) and reversible posterior leukoencephalopathy (one case) in a patient initially diagnosed with cystic fibrosis. This patient was on cyclosporine and showed neurological symptoms eight days after the procedure, progressing to acute subdural hemorrhage. Currently, he has motor neurological deficit without other complications.
In our study, the most common infection found after the first month of transplant was due to citomegalovirus (CMV), followed by respiratory viral infections and bacterial infections.
Figure 2 shows the survival rate based on the time after transplantation for patients 18 years old and younger.
DISCUSSION
LTx is a well-established therapy for patients with chronic lung disease and end-stage vascular
pulmonary disease. Indications for LTx in the pediatric population are rare because terminal
illnesses in this age group are uncommon (55. Huddleston CB. Pediatric lung transplantation. Curr Treat Options Cardiovasc.
Med. 2011;13(1):68-78, http://dx.doi.org/10.1007/s11936-010-0105-6.
http://dx.doi.org/10.1007/s11936-010-010...
). Most patients
younger than 18 years who undergo lung transplantation are older than 11 years (3,6), which was also
found in our study group.
The main indications for LTx in the pediatric population are pulmonary cystic fibrosis,
interstitial lung disease associated with pulmonary fibrosis, and congenital vascular disease (44. Yusen RD, Christie JD, Edwards LB, Kucheryavaya AY, Benden C, Dipchand AI, et al.
The Registry of the International Society for Heart and Lung Transplantation: thirtieth adult lung
and heart-lung transplant report—2013; focus theme: age. J Heart Lung Transplant.
2013;32(10):965-78, http://dx.doi.org/10.1016/j.healun.2013.08.007.
http://dx.doi.org/10.1016/j.healun.2013....
,55. Huddleston CB. Pediatric lung transplantation. Curr Treat Options Cardiovasc.
Med. 2011;13(1):68-78, http://dx.doi.org/10.1007/s11936-010-0105-6.
http://dx.doi.org/10.1007/s11936-010-010...
). Furthermore, in
Brazil, the prevalence of bronchiectasis (not secondary to cystic fibrosis) is considerable, and
this condition frequently requires LTx.
In the adult population, the main indications are emphysema and idiopathic pulmonary fibrosis
(44. Yusen RD, Christie JD, Edwards LB, Kucheryavaya AY, Benden C, Dipchand AI, et al.
The Registry of the International Society for Heart and Lung Transplantation: thirtieth adult lung
and heart-lung transplant report—2013; focus theme: age. J Heart Lung Transplant.
2013;32(10):965-78, http://dx.doi.org/10.1016/j.healun.2013.08.007.
http://dx.doi.org/10.1016/j.healun.2013....
).
The pediatric contraindications for the procedure are identical to those in the adult population
and include systemic diseases with extrapulmonary complications, malignancy, HIV infection, and
severe renal impairment. The absence of social support, transportation issues, or poor adherence to
treatment are also important conditions that preclude LTx (77. Orens JB, Estenne M, Arcasoy S, Conte JV , Corris P, Egan JJ, et al.
International guidelines for the selection of lung transplant candidates: 2006 update—a
consensus report from the Pulmonary Scientific Council of the International Society for Heart and
Lung Transplantation. J. Heart Lung Transplant. 2006;25(7):745-55,
http://dx.doi.org/10.1016/j.healun.2006.03.011.
http://dx.doi.org/10.1016/j.healun.2006....
).
The number of pediatric transplants performed in our study group, although small, corresponded to
approximately 5.7% of the total number of transplants performed, which did not differ from the
literature (33. Benden C, Edwards LB, Kucheryavaya AY, Christie JD, Dipchand AI, Dobbels F, et
al. The Registry of the International Society for Heart and Lung Transplantation: sixteenth official
pediatric lung and heart-lung transplantation report—2013; focus theme: age. J Heart
Lung Transplant. Elsevier; 2013;32(10):989-97,
http://dx.doi.org/10.1016/j.healun.2013.08.008.
http://dx.doi.org/10.1016/j.healun.2013....
). The survival rate was also similar to that of
the international registry, but a longer follow-up is necessary, as illustrated by the patient with
a longer follow-up who underwent surgery 5 years earlier.
The low number of donors and viable organs for donation is a significant complicating factor that has affected the pediatric and adult LTx program.
As in the adult population, there are three main types of postoperative complications: immediate
complications, occurring in the first days after transplantation; early complications, occurring
within three months posttransplantation; and late complications (88. Solomon M, Grasemann H, Keshavjee S. Pediatric lung transplantation. Pediatr.
Clin North Am. 2010;57(2):375-91, http://dx.doi.org/10.1016/j.pcl.2010.01.017.
http://dx.doi.org/10.1016/j.pcl.2010.01....
).
The immediate postoperative complications are hyperacute rejection, primary graft dysfunction, reperfusion injury, and surgical complications, such as anastomotic dehiscence and bleeding.
Hyperacute rejection is an uncommon condition. Today, virtual crossmatching performed
preoperatively in patients with a high reactive panel identifies any possible incompatibility that
could preclude transplantation between the recipient and donor. Hyperacute rejection has a poor
prognosis, and treatment should be started immediately if the prospective crossmatch is positive.
The treatment consists of plasmapheresis in the operating room and during the postoperative period,
with the administration of intravenous immunoglobulin and thymoglobulin as an additional potential
indication for retransplantation (88. Solomon M, Grasemann H, Keshavjee S. Pediatric lung transplantation. Pediatr.
Clin North Am. 2010;57(2):375-91, http://dx.doi.org/10.1016/j.pcl.2010.01.017.
http://dx.doi.org/10.1016/j.pcl.2010.01....
,99. Frost AE, Jammal CT, Cagle PT. Hyperacute rejection following lung
transplantation. Chest. 1996;110(2):559-62,
http://dx.doi.org/10.1378/chest.110.2.559.
http://dx.doi.org/10.1378/chest.110.2.55...
).
Another important complication is primary graft dysfunction, which occurred in our setting and
can occur within 72 hours post-surgery. Primary graft dysfunction is defined by a low relationship
between PaO2 and FiO2, with or without radiographic changes. The complication is described in Table 1. International data show that cardiopulmonary bypass
is used more frequently in pediatric LTx compared with adult LTx, and its use is related to the
development of primary graft dysfunction, smoking status of the donor, presence of reperfusion
injury, and body mass index of the recipient (88. Solomon M, Grasemann H, Keshavjee S. Pediatric lung transplantation. Pediatr.
Clin North Am. 2010;57(2):375-91, http://dx.doi.org/10.1016/j.pcl.2010.01.017.
http://dx.doi.org/10.1016/j.pcl.2010.01....
,1010. Christie JD, Carby M, Bag R, Corris P, Hertz M, Weill D. Report of the ISHLT
Working Group on Primary Lung Graft Dysfunction part II: definition. A consensus statement of
the International Society for Heart and Lung Transplantation. J Heart Lung Transplant.
2005;24(10):1454-9, http://dx.doi.org/10.1016/j.healun.2004.11.049.
http://dx.doi.org/10.1016/j.healun.2004....
,1111. Diamond JM, Lee JC, Kawut SM, Shah RJ, Localio AR , Bellamy S, et al. Clinical
risk factors for primary graft dysfunction after lung transplantation. Am J Respir Crit
Care Med. 2013;187(5):527-34, http://dx.doi.org/10.1164/rccm.201210-1865OC.
http://dx.doi.org/10.1164/rccm.201210-18...
). In acute respiratory
distress syndrome, clinical management consists of protective ventilation and, in some cases, the
use of extracorporeal membrane oxygenation (1010. Christie JD, Carby M, Bag R, Corris P, Hertz M, Weill D. Report of the ISHLT
Working Group on Primary Lung Graft Dysfunction part II: definition. A consensus statement of
the International Society for Heart and Lung Transplantation. J Heart Lung Transplant.
2005;24(10):1454-9, http://dx.doi.org/10.1016/j.healun.2004.11.049.
http://dx.doi.org/10.1016/j.healun.2004....
,1212. Pego-Fernandes P, Hajjar L, Galas F, Samano M, Ribeiro A, Park M, et al.
Respiratory failure after lung transplantation: extracorporeal membrane oxygenation as a rescue
treatment. Clinics. 2012;67(12):1529-32,
http://dx.doi.org/10.6061/clinics/2012(12)32.
http://dx.doi.org/10.6061/clinics/2012(1...
,1313. Barbas CSV, Matos GFJ, Amato MBP, Carvalho CRR. Goal-oriented respiratory
management for critically ill patients with acute respiratory distress syndrome. Crit Care Res
Pract. 2012:952168.).
Classification of Primary graft dysfunction - Adapted from ISHLT (International Society of Heart and Lung Transplantation Registries) (10).
Acute rejection, infection, side effects of immunosuppressive drugs, and surgical complications, such as stenosis of the bronchial anastomosis, are some immediate postoperative complications; they frequently occur in the first three months after LTx.
Clinically, diagnosing acute rejection and respiratory infections can be challenging, and they
require different treatments. The diagnosis of acute rejection is made using histological findings
that show perivascular mononuclear cell infiltrate. The intensity and extent of the acute rejection
determines its classification (1414. Stewart S, Fishbein MC, Snell GI, Berry GJ, Boehler A, Burke MM, et al. Revision
of the 1996 working formulation for the standardization of nomenclature in the diagnosis of lung
rejection. J Heart Lung Transplant. 2007;26(12):1229-42,
http://dx.doi.org/10.1016/j.healun.2007.10.017.
http://dx.doi.org/10.1016/j.healun.2007....
). When indicated, treatment
consists of adjusting the immunosuppression, including changing or increasing the dose of the
immunosuppressive maintenance regimen, administering high doses of corticosteroids (in some cases),
and using intravenous thymoglobulin in more severe or refractory cases (1515. Snell GI, Boehler A, Glanville AR, McNeil K, Scott JP, Studer SM, et al. Eleven
years on: a clinical update of key areas of the 1996 lung allograft rejection working formulation.
J. Heart Lung Transplant. 2007;26(5):423-30,
http://dx.doi.org/10.1016/j.healun.2007.01.040.
http://dx.doi.org/10.1016/j.healun.2007....
). The infection treatment is based on etiological agents.
Infections are often related to the use of immunosuppressive drugs, and infections are one type
of complication that can be present during the entire posttransplant follow-up period. The use of
maintenance medications has other undesirable effects, including metabolic changes (hyperglycemia
and dyslipidemia) and nephrotoxicity. In our study group, one patient had reversible posterior
leukoencephalopathy, a disease that is often associated with the use of calcineurin inhibitors and
that has variable outcomes (1616. McKinney AM, Short J, Truwit CL, McKinney ZJ, Kozak OS, SantaCruz KS, et al.
Posterior reversible encephalopathy syndrome: incidence of atypical regions of involvement and
imaging findings. AJR Am J Roentgenol. 2007;189(4):904-12,
http://dx.doi.org/10.2214/AJR.07.2024.
http://dx.doi.org/10.2214/AJR.07.2024...
,1717. Pedraza R, Marik PE, Varon J. Posterior Reversible Encephalopathy Syndrome: A
Review. 2009;12(4):135-43.). It involves a wide spectrum of neurological manifestations, such as a
decreased level of consciousness, seizures, and visual disturbances that are frequently associated
with ischemic changes mainly in parietal and occipital lesions, as evidenced by MRI. The
reversibility of lesions is case dependent. Patient management usually consists of reducing or
changing the calcineurin inhibitor. Our case showed reversibility of the changes after the initial
change in the immunosuppressant agent, but the patient developed hemorrhagic transformation and
persistent motor deficiency.
Bronchiolitis obliterans syndrome is the main late complication; it corresponds to chronic graft
dysfunction. Bronchiolitis obliterans syndrome is defined by a 20% drop in the forced expiratory
volume (FEV1) value in one second compared with the patient's baseline, and it is diagnosed
using the best three FEV1 values previously taken after the development of fixed airflow obstruction
on spirometry and in the absence other factors that may influence the collection method (1818. Todd JL, Palmer SM. Bronchiolitis obliterans syndrome: the final frontier for
lung transplantation. Chest. 2011;140(2):502-8,
http://dx.doi.org/10.1378/chest.10-2838.
http://dx.doi.org/10.1378/chest.10-2838...
). The differential diagnosis includes other causes of FEV1
decline, such as anastomotic stenosis or respiratory infections. In some cases, the patient may
present with severe dysfunction and end-stage pulmonary disease, and any indication for
retransplantation should be carefully evaluated (55. Huddleston CB. Pediatric lung transplantation. Curr Treat Options Cardiovasc.
Med. 2011;13(1):68-78, http://dx.doi.org/10.1007/s11936-010-0105-6.
http://dx.doi.org/10.1007/s11936-010-010...
). In our
study group, retransplantation was indicated three years after the first procedure in a patient who
underwent transplantation at age 16.
The indications for LTx in a pediatric population are less common than those in an adult population. Certain peculiarities, such as the prevalence of different diseases, indicate the procedure and direct its perioperative management, although the postoperative complications and treatments are similar to those found in patients older than 18. In our setting, the indications, prevalence of pediatric LTx, and survival rates were similar to those in the international data, despite the small number of patients.
REFERENCES
-
1Hardy JD. Lung Homotransplantation in Man. JAMA. 1963;186(12):1065-74, http://dx.doi.org/10.1001/jama.1963.63710120001010.
» http://dx.doi.org/10.1001/jama.1963.63710120001010 -
2Mendeloff EN. The history of pediatric heart and lung transplantation. Pediatr Transplant. 2002;6(4):270-9, http://dx.doi.org/10.1034/j.1399-3046.2002.00217.x.
» http://dx.doi.org/10.1034/j.1399-3046.2002.00217.x -
3Benden C, Edwards LB, Kucheryavaya AY, Christie JD, Dipchand AI, Dobbels F, et al. The Registry of the International Society for Heart and Lung Transplantation: sixteenth official pediatric lung and heart-lung transplantation report—2013; focus theme: age. J Heart Lung Transplant. Elsevier; 2013;32(10):989-97, http://dx.doi.org/10.1016/j.healun.2013.08.008.
» http://dx.doi.org/10.1016/j.healun.2013.08.008 -
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» http://dx.doi.org/10.1016/j.healun.2013.08.007 -
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» http://dx.doi.org/10.1007/s11936-010-0105-6 -
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» http://dx.doi.org/10.1016/j.healun.2006.03.011 -
8Solomon M, Grasemann H, Keshavjee S. Pediatric lung transplantation. Pediatr. Clin North Am. 2010;57(2):375-91, http://dx.doi.org/10.1016/j.pcl.2010.01.017.
» http://dx.doi.org/10.1016/j.pcl.2010.01.017 -
9Frost AE, Jammal CT, Cagle PT. Hyperacute rejection following lung transplantation. Chest. 1996;110(2):559-62, http://dx.doi.org/10.1378/chest.110.2.559.
» http://dx.doi.org/10.1378/chest.110.2.559 -
10Christie JD, Carby M, Bag R, Corris P, Hertz M, Weill D. Report of the ISHLT Working Group on Primary Lung Graft Dysfunction part II: definition. A consensus statement of the International Society for Heart and Lung Transplantation. J Heart Lung Transplant. 2005;24(10):1454-9, http://dx.doi.org/10.1016/j.healun.2004.11.049.
» http://dx.doi.org/10.1016/j.healun.2004.11.049 -
11Diamond JM, Lee JC, Kawut SM, Shah RJ, Localio AR , Bellamy S, et al. Clinical risk factors for primary graft dysfunction after lung transplantation. Am J Respir Crit Care Med. 2013;187(5):527-34, http://dx.doi.org/10.1164/rccm.201210-1865OC.
» http://dx.doi.org/10.1164/rccm.201210-1865OC -
12Pego-Fernandes P, Hajjar L, Galas F, Samano M, Ribeiro A, Park M, et al. Respiratory failure after lung transplantation: extracorporeal membrane oxygenation as a rescue treatment. Clinics. 2012;67(12):1529-32, http://dx.doi.org/10.6061/clinics/2012(12)32.
» http://dx.doi.org/10.6061/clinics/2012(12)32 -
13Barbas CSV, Matos GFJ, Amato MBP, Carvalho CRR. Goal-oriented respiratory management for critically ill patients with acute respiratory distress syndrome. Crit Care Res Pract. 2012:952168.
-
14Stewart S, Fishbein MC, Snell GI, Berry GJ, Boehler A, Burke MM, et al. Revision of the 1996 working formulation for the standardization of nomenclature in the diagnosis of lung rejection. J Heart Lung Transplant. 2007;26(12):1229-42, http://dx.doi.org/10.1016/j.healun.2007.10.017.
» http://dx.doi.org/10.1016/j.healun.2007.10.017 -
15Snell GI, Boehler A, Glanville AR, McNeil K, Scott JP, Studer SM, et al. Eleven years on: a clinical update of key areas of the 1996 lung allograft rejection working formulation. J. Heart Lung Transplant. 2007;26(5):423-30, http://dx.doi.org/10.1016/j.healun.2007.01.040.
» http://dx.doi.org/10.1016/j.healun.2007.01.040 -
16McKinney AM, Short J, Truwit CL, McKinney ZJ, Kozak OS, SantaCruz KS, et al. Posterior reversible encephalopathy syndrome: incidence of atypical regions of involvement and imaging findings. AJR Am J Roentgenol. 2007;189(4):904-12, http://dx.doi.org/10.2214/AJR.07.2024.
» http://dx.doi.org/10.2214/AJR.07.2024 -
17Pedraza R, Marik PE, Varon J. Posterior Reversible Encephalopathy Syndrome: A Review. 2009;12(4):135-43.
-
18Todd JL, Palmer SM. Bronchiolitis obliterans syndrome: the final frontier for lung transplantation. Chest. 2011;140(2):502-8, http://dx.doi.org/10.1378/chest.10-2838.
» http://dx.doi.org/10.1378/chest.10-2838
-
No potential conflict of interest was reported.
Publication Dates
-
Publication in this collection
Jan 2014