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Lung Transplant in Children With Cystic Fibrosis

Lung Transplant in Children With Cystic Fibrosis

Lung transplant is the standard treatment for children with end-stage lung disease as a result of CF. But do the benefits of transplant outweigh the risks of early rejection-related mortality in these children?

Ingrid M. Pitts, PA-C

Vol. 16 • Issue 12 • Page 41
Cystic fibrosis (CF) is an autosomal recessive monogenic disorder that affects multiple organ systems.1 The gene responsible for CF is located on chromosome 7, and in 1989 it was discovered that it encodes the molecular mutations in the CF transmembrane conductance regulator (CFTR) protein.1,2 CFTR regulates epithelial cell transport of sodium ions and chloride ions in the respiratory tract, the gastrointestinal tract, the sweat glands and the genitourinary system.1

Upper respiratory tract disease is common in most CF patients. Chronic cough and repeated infections lead to bronchiectasis, bronchiolectasis and, ultimately, respiratory failure.1 Most patients with CF die prematurely because of repeated lung infections with Gram-negative bacteria, which leads to respiratory insufficiency.3


About 30,000 people in the United States have CF.4 About 1,000 new cases are diagnosed each year in the United States, and more than 70% of CF patients are diagnosed by age 2.5 CF can affect people of any race but is most common in Caucasians.4

CF once was considered exclusively a pediatric disease; however, it can be diagnosed in adults.4 Until the mid-20th century, patients diagnosed with CF had short survival expectancies; however, as the disease has become better understood and as treatment has improved, survival expectancies have increased.1 Now, more than 40% of the CF patient population is 18 or older.5 The Cystic Fibrosis Foundation reports the predicted median age of survival of a person with CF to be now more than 37 years.5

Lung Transplant and CF

The focus of this article is limited to CF characteristics pertaining to the lungs, and treatment with lung transplantation. Treatments for pulmonary manifestations are aimed at clearing mucus secretions and controlling infections. Lung transplant is an option for patients with CF that results in end-stage disease.6 The first lung transplant was performed in 1963 at the University of Mississippi,7 and the first lung transplant in a CF patient was performed in 1983 at the University of Pittsburgh.2

Posttransplantation complications include infections; the side effects of immunosuppressants; other underlying diseases, such as sarcoidosis and cancer; and acute and chronic rejection, which ultimately lead to bronchiolitis obliterans (BO). Rejection occurs because the body recognizes the donor lung as foreign, and the immune system fights to rid the body of it. Alloreactive cytotoxic T-lymphocyte-mediated endothelial damage or bronchiolar epithelial damage results in rejection.8

Half or more of patients experience at least one episode of acute rejection in the first year after transplantation.6,9 As many as 54% of lung transplant recipients eventually develop progressive chronic rejection-continuous breakdown of the graft lung and associated scarring-leading to BO.10

Scarring develops when airway submucosal mononuclear cells infiltrate the basement membrane and enter the epithelium. The epithelial cells then break down and cause fibroblasts and myofibroblasts to migrate to the submucosa of the bronchioles. Granulation develops and ultimately renders the donor lung nonfunctional.

Immunosuppressants, in conjunction with antibiotics, are used for induction and as a maintenance regimen for the rest of the recipient's life. Most transplant recipients are managed with a three-drug regimen of a calcineurin inhibitor (i.e., cyclosporine or tacrolimus), a purine antagonist (i.e., azathioprine or mycophenolate mofetil) and prednisone.6

In a child with CF, the decision about lung transplantation for end-stage disease can be daunting. Rejection and other transplantation complications can increase the already higher risk of early mortality in CF patients. The benefits of lung transplant in children with CF and the increased risk of early mortality must be carefully assessed.

Survival Rates and Transplant

In one study, Geertsma and colleagues assessed the effects of lung transplantation on survival of patients with end-stage lung disease.11 From November 1990 to January 1996, the lung transplant program at a hospital in the Netherlands prospectively analyzed 157 patients on the transplantation waiting list, 76 of whom underwent transplantation. All of the subjects had a predicted life expectancy of less than 12 to 18 months without transplantation.

By Jan. 31, 1996, 17 patients had died posttransplantation, most of whom died as a result of BO. The 47 patients still on the waiting list at that time served as control subjects. Ultimately, 33 of these patients died. The mean age of all 157 patients was 41 years.

The authors note that the study's limitations include conservative estimates resulting from differences in the two groups. Additionally, the sample size of 157 patients is small. Nevertheless, the authors found that the one-, three- and five-year survival rates were 85%, 73% and 70%, respectively, for patients who received a lung transplant. The one- and two-year survival rates for subjects on the waiting list who died or who waited until a lung was available were 78% and 58%, respectively. They also noted that transplantation reduced the risk of death by 55%.

The results suggest that the predicted life expectancy would have been less than 12 to 18 months without transplantation. In comparison, 73% of patients undergoing transplantation were still alive at three years, suggesting that transplantation extends life expectancy.

In another study, Huddleston and colleagues evaluated the practicality of lung transplantation in children.12 They analyzed 207 lung transplants in 190 children younger than 18 from 1990 to 2002 at the St. Louis Children's Hospital transplant program in Missouri. The patients were followed on average for 3.5 years posttransplantation and had a life expectancy of less than two years prior to transplantation. Eighty-nine of the patients had CF.

The 166 recipients who were followed for more than six months experienced an average of 1.95 rejections. Of these 166 subjects, 84 had BO, which was the leading cause of death in the long term. A smaller percentage of recipients of lungs with ischemic times of less than two hours went on to BO than did recipients of lungs with ischemic times of more than two hours. Posttransplantation survival rates at one, three and five years were 77%, 63% and 54%, respectively.

The results suggest that the predicted life expectancy of these patients would have been two years hadthey not received a transplant. In comparison, 63% of the posttransplantation patients were still alive at three years, implying an increased life expectancy with transplantation.

The sample size of 190 patients is small and creates limitations of the study; nevertheless, at that time, this was the largest series of pediatric lung transplants in the world.

Transplant Extends Life

Aurora and colleagues evaluated the effects of lung or lung-heart transplantation on the survival of children from ages 4 to 19 years with CF and other severe lung diseases.13 Between May 1988 and May 1998, 124 children, all with a life expectancy less than two years, were accepted for lung transplant at the Great Ormond Street Hospital transplant program for children in London. Of the 124 children, 47 received transplants, 68 died waiting and nine remained on the list after the study period ended.

Of the 47 recipients, 28 died. While the reasons for death-whether infection, rejection or BO-were not provided, the survival rates at one, two and five years were 74%, 66% and 33%, respectively. The authors also noted a 69% reduction in overall risk of death. Predicted life expectancy of two years without transplantation compared with a two-year posttransplantation survival rate of 66% suggests that transplantation extends life.

Among the authors' identified study limitations are the incomparable groups (because random selection was not possible) and prioritization (the sickest patients received transplants first). Furthermore, the sample size of 124 is small.

Egan and colleagues tried to identify factors influencing long-term survival of 123 patients with CF in the lung transplantation program at the University of North Carolina at Chapel Hill.14 All 123 patients received transplantation during the 10 years between 1990 and 2001. Nine recipients had living donors, while the rest had double lung transplant from cadavers.

The authors evaluated the impact of age on survival and found no difference in survival estimates between patients younger than 20 years old and patients older than 20. BO caused 50% of deaths after the first year of transplant. By the end of the follow-up period, 53 posttransplantation CF patients had died as a result of multiple complications, including BO.

Bacterial infection was the most dominant cause of death within the first posttransplantation year. Recipients who were not colonized with Burkholderia cepacia prior to transplant were found to have an 86% survival rate. Although BO-related deaths were significant, the authors reported one-, five- and 10-year survival rates of 81%, 58% and 36%, respectively. They also noted that more patients died on the waiting list than who received transplants.

Further Studies Concur

To examine the long-term outcome of lung transplantation, de Perrot and colleagues reviewed 521 lung transplants in 501 patients between the ages of 8 and 71 with end-stage lung disease.7 Patients had estimated life expectancies before transplant of less than 2 years and received transplants at Toronto General Hospital between 1983 and 2003. Children younger than 18 comprised 22% of the total cohort. Of the 501 patients, 124 had CF and received bilateral lung transplantation.

The five-, 10- and 15-year survival rates were 55.1%, 35.3% and 26.5%, respectively, with better survival outcomes for CF patients without B. cepacia infection than CF patients with it. Negative B. cepacia CF patients' five- and 10-year survival was 76% and 52%, respectively. BO was the third cause of mortality, with sepsis and graft failure predominantly responsible for most deaths (36% and 29%, respectively).

The results imply that BO was not as significant mortality concern as were other complications, implying that lung transplantation increases life expectancy.

Bech and colleagues id a retrospective study of 47 patients with CF accepted for transplant at a hospital in Copenhagen, Denmark, from 1992 to 2003.3 The patients' ages ranged from 11 to 50, and all had an estimated life expectancy of less than two years. Twenty-nine received transplantation, and 18 died while awaiting organs.

The authors found that the survival of transplant at one, three, five and eight years was 89%, 80%, 80% and 70%, respectively. Only two patients died of BO. Posttransplantation survival rates for patients without BO at one, three and five years were 90%, 77% and 60%, respectively. Those still awaiting lung transplants survived an average of 189 days, and the one- and two-year survival rates were 28% and 11%, respectively.

The 47-patient sample size cannot provide a strong representation of the population; nevertheless, a three-year survival rate of 77% is quite significant.

A team led by Venuta reviewed 102 patients who received lung transplants at a transplant program in Rome, Italy.15 They evaluated the effects of bilateral sequential lung transplant for patients with CF from 1996 to 2002. Patients' ages ranged from 7 to 51 years. Fifty-six patients received transplants, and 34 died while on the waiting list. By the end of the reviewed period, 12 were still on the waiting list.

In the first year posttransplantation, acute rejection occurred an average of 1.6 times per patient, and BO occurred in only 15 patients. The overall two-year survival rate was 79%. This relatively high percentage likely relates to a very small sample size; regardless of this limitation, the authors concluded that lung transplant does improve survival.

A team led by Quattrucci evaluated 114 patients with CF who had been referred to their lung transplant program in Rome, Italy.16 Between October 1996 and October 2002, they evaluated posttransplantation survival and incidence of rejection and BO. Of the 114 referrals, 99 were placed on the waiting list. Thirty-five died while waiting for an organ, and 55 (six of whom were children) received bilateral sequential transplants.

Survival rates at one month, three years and six years were 80%, 70% and 58%, respectively. All told, 95% of patients stayed free of BO at one year, 82.5% at two years, 70% at three years and 65% at four, five and six years posttransplantation.

Not All Research Agrees

Liou and colleagues used a retrospective observational cohort study of 11,630 CF patients whose information was gathered from the Cystic Fibrosis Foundation Patient Registry (CFFPR) from 1992 to 1998.17 They sought to identify the impact of bilateral lung transplant on survival of patients with CF. These patients did not receive transplants but were used as a control group against 468 transplanted patients from centers across the United States.

Based on a five-year survivorship predictor model that the authors developed and described elsewhere,18 patients in the transplantation and control groups were placed into one of five subgroups: subjects with survival predicted at less than 30% were placed in group 1; 30% to 49% in group 2; 50% to 69% in group 3; 70% to 89% in group 4; and 90% to 100% in group 5.

In contrast to other studies described here, the Liou and colleagues study indicates that only a minority of CF patients benefit from lung transplantation. Patients with a predicted five-year survival less than 30% were the only group to demonstrate improved outcomes. In fact, the remaining groups had equivocal or reduced five-year survival rates.

Limiting the study is that most of the survival estimates were based on data from the CFFPR. Patients on the registry were used as the control group, but those who died while waiting for transplant were not included in the data. This approach could have skewed the data to the disadvantage of positive survival effects.

Analysis of the Literature

Some of the most significant studies of lung transplantation and rejection have been performed in the United States and Europe. All the studies reviewed here are a compilation of retrospective or prospective observational cohorts reviewing patient progress to evaluate the benefits of lung transplant in adults and children with CF. After 1970, the trend in the literature has been to use patients on waiting lists as control groups.11

Similar statistical measures are used in all the cited studies. While relatively few studies offer 10- and 20-year outcomes for transplanted patients, most studies reveal a decreased percentage of survival as the years progressed; nevertheless, these percentages were better than those of the estimated survival before transplantation.

One of the most significant observations reported in a number of studies is that if CF were better understood, outcome results could be influenced positively. If CF were categorized in progressive stages, patients in need of transplantation would be more easily identified. Another observation was that lung donation is limited, negatively impacting life expectancy data. If more donors were available, high-risk patients would have more opportunities to receive transplants.

A number of vital considerations were lacking in the literature reviewed. First, although the literature did not provide documentation of any direct harm resulting from lung transplantation, there was a lack of analysis of the potential risk of lung transplantation. Second, there was a lack of analysis of potential untoward effects of the donor organ itself. A few studies considered the influence on survival from using single, double or lobar transplants. Some reported the influence of the donor lung size, but few evaluated the effects of the mode of organ transportation. Only one mentioned the concern for preservation or ischemic time between donor and recipient. Third, there is much room for more analysis of quality of life posttransplantation.

Furthermore, one population has been unexplored throughout the literature: End-stage lung disease patients who do not want transplantation are not on waiting lists and therefore are not included in the data. The literature does not explain the impact of this unaccounted for population on outcomes.

Other limitations of the cited studies include small sample size, conservative estimates, prioritizing patient selections for transplantation and the inability to quantify quality of life after transplantation. Despite these limitations, the articles conclude that lung transplantation does extend life expectancy. Rejection resulting in BO is most concerning after lung transplantation; however, the literature implies that infections are far more responsible for mortality. With the exception of one report from Liou and colleagues,17 of which data for the conclusion were not provided, all studies reported a benefit of lung transplant in CF patients.


The Registry of the International Society for Heart and Lung Transplantation includes data from more than two dozen pediatric lung transplant centers.19 These data reveal that more than 60% of pediatric lung transplants are performed in teenagers, with most recipients ranging in age from 12 to 17 years. CF is most diagnosed during childhood and adolescence and is the underlying diagnosis of 56% of all pediatric lung transplants.19

The data further show that survival in the pediatric population is the same as that of the adult population, and that pediatric survival was better from 2000 to 2004 compared with 1988 to 1994. Infants have a better survival rate than recipients aged 12 to 17, and concern is increasing about the complication of BO. Rejection was not the leading cause of mortality within the first year posttransplantation; however, BO was the leading cause of death after one year (40%) and after seven years (32%).

According to the United Network for Organ Sharing, more than 100,000 patients are on U.S. waiting lists for organ transplantation.20 More than 2,000 patients await lungs, of whom more than 300 are waiting as a result of CF.21 More than 17,000 lung transplants have been performed in the United States since 1988.20 More than 800 of these transplants have been in patients 17 and younger.21

Transplant Eligibility

Prior criteria for referral timing and lung allocation have influenced the outcome of transplanted and nontransplanted CF patients. It is difficult for primary care providers to know when to refer patients for transplantation, because CF is a multisystem disease without a categorized staging system to identify progression.

Historically, patients' eligibility to undergo lung transplantation was determined solely by the forced expiratory volume in one second (FEV1.17 If FEV1 as 30% or less for a CF patient, then the two-year mortality rate was considered 50% or greater.17 The patient then would be considered for lung transplantation. However, this method may not identify the sickest patients in order to facilitate referral and transplantation.

The same problem existed when allocation was predicted by length of time spent on a waiting list. Retrospective observational cohort studies that assessed survivorship and effectiveness of lung transplantation used data collected from the Cystic Fibrosis Foundation Patient Registry to determine that more clinical features are necessary to identify gravely ill patients.17,18

The following clinical features of CF wereanalyzed and determined to aid in the process of gravely ill patient identification: age, FEV1 sex, weight-for-age Z score, pancreatic sufficiency, diabetes, Staphylococcus aureus infection, B. cepacia infection and the annual number of acute pulmonary exacerbations.18 The Organ Procurement Network and the United Network for Organ Sharing observed these considerations, and the method for referral and allocation has been modified since 2005.

Aside from FEV1 other variables are included in the equation on determining who is more acutely eligible for transplantation. An allocation score is now given to all lung transplant candidate aged 12 and older, grading them from sick to deathly ill using multiple clinical symptoms. Pediatric and adolescent candidates are prioritized when the donor is the same age.

Referral timing also is important and affects the survival outcome data. A 2006 updated census report from the Pulmonary Scientific Council of the International Society for Heart and Lung Transplantation suggests that guidelines for referral include FEV1below 30% of predicted or a rapid decline in FEV1(particularly in young women), exacerbations of pulmonary disease requiring ICU stay, increasing frequency of exacerbations requiring antibiotic therapy, refractory and/or recurrent pneumothorax and recurrent hemoptysis not controlled by embolization22. They suggest that transplantation in CF patients should occur when the patient has oxygen-dependent respiratory failure, hypercapnia or pulmonary hypertension.22 If the sickest patients are identified, referred and receive lung transplants, the number of deaths of patients on waiting lists would be reduced. This reduction would influence survival outcome data in the comparison between transplanted and nontransplanted patients.

Potential New Therapies

A number of potential treatments to improve CF outcomes are under investigation.23 The discovery of the CFTR protein responsible for CF has propelled multiple scientific investigations in gene therapy. Using gene therapy, the abnormal gene might be replaceable with normal ones, thereby eradicated the disease. The function of the defective CFTR protein could be corrected, which would facilitate proper chloride and sodium ion transport within cells, creating better linings for the lungs and other involved organs.

Other investigations have targeted mucus secretion. Trials evaluating the use of dornase alfa and hypotonic solution are ongoing to evaluate the efficacy of mucus clearing, while others are investigating the use of pharmaceuticals to restore salt transportation-by correcting the amount of salt within the cell surface, the mucus thickness can be hydrated.

Trials of agents that target the body's immune system and inflammation are being conducted, including ones on oral N-acetylcysteine; docosahexaenoic acid; low-dose methotrexate; pioglitazone and hydroxychloroquine; simvastatin, inhaled glutathione; and HE 2000 (16 alpha-bromoepiandrosterone). Inhaled cyclosporine is being evaluated for its efficacy in CF patients.

Other area of potential future improvement for CF patient outcome lies in reducing infections. Studies are ongoing on drugs such as tobramycin inhalation solution and inhaled powder, azithromycin, aztreonam, inhaled ciprofloxacin, sustained-release lipid inhaled targeting (SLIT) amikacin, MP-610.205, KaloBios KB001 and pseudomonas vaccinations.

Nutritional supplements also are being investigated as future treatment. Trials for CF patients are currently under way to test pancreatic enzyme replacements and a specially formulated antioxidant vitamin for CF patients.

Surgical techniques and photopheresis also are being explored. Procedures such as split-lung and reduced-lung techniques now are being implemented.15 ise and colleagues report that extracorporeal photopheresis could be an option for the treatment of rejection in lung transplant patients.24 It has been used with positive effects in 150 transplant centers worldwide for the treatment of rejection in heart and kidney transplant. he therapeutic concept is removing the leukocyte fraction from whole blood and treating it with ultraviolet A light. This treated blood is then reintroduced into the patient. The mechanism of action is unknown, but clinical studies have reported a reduction of lymphocytes active in rejection, suggesting that the procedure may be a new antirejection therapy for CF patients who have undergone lung transplantation.

Transplant Risks and Benefits

The survival outcome of lung transplantation depends on many factors. Age, patient size, transplant waiting list timing, cadaver or living donor, bacterial culture before transplant, immunosuppressant regimen before and after transplant, referral, lung allocation and rejection all play a role in survival. Although chronic rejection can lead to BO, it is responsible for only about one-third of worldwide pediatric deaths after seven years posttransplantation.

The literature implies that lung transplantation remains an acceptable option for the treatment of end-stage lung disease caused by CF in children. Overall, it appears that the benefits of lung transplant for children with CF-related end-stage lung disease outweighs the risk of early mortality related to rejection. Although the risk of rejection and BO are significant, it does not seem to be an overwhelming hindrance to having lung transplantation.

As the disease is better understood, as donors increase and as allocation, treatment and patient identification improve, life expectancy for these patients also will improve. Patients and their families should feel confident using the current data to help in the decision-making process to determine if lung transplantation is suitable for them.


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4. Frequently asked questions. Cystic Fibrosis Foundation. http://www.cff.org/AboutCF/Faqs. Updated May 15, 2007. Accessed November 17, 2008.

5. About cystic fibrosis.Cystic Fibrosis Foundation. http://www.cff.org/AboutCF. Accessed November 17, 2008.

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7. de Perrot M, Chaparro C, McRae K, et al. Twenty-year experience of lung transplantation at a single center: influence of recipient diagnosis on long-term survival. J Thorac Cardiovasc Surg. 2004;127(5):1493-1501.

8. Longchampt E, Achkar A, Tissier F, Rabbat A, Audouin J, Molina TJ. Coexistence of acute cellular rejection and lymphoproliferative disorder in a lung transplant patient. Arch Pathol Lab Med. 2001;125(11):1500-1502.

9. al-Dossari GA, Kshettry VR, Jessurun J, Bolman RM III. Experimental large-animal model of obliterative bronchiolitis after lung transplantation. Ann Thorac Surg. 1994;58(1):34-40.

10. Kramer MR, Stoehr C, Whang JL, et al. The diagnosis of obliterative bronchiolitis after heart-lung and lung transplantation: low yield of transbronchial lung biopsy. J Heart Lung Transplant. 1993;12(4):675-681.

11. Geertsma A, Ten Vergert EM, Bonsel GJ, de Boer WJ, van der Bij W. Does lung transplantation prolong life? A comparison of survival with and without transplantation. J Heart Lung Transplant. 1998;17(5):511-516.

12. Huddleston CB, Bloch JB, Sweet SC, de la Morena M, Patterson GA, Mendeloff EN. Lung transplantation in children. Ann Surg. 2002;236(3):270-276.

13. Aurora P, Whitehead B, Wade A, et al. Lung transplantation and life extension in children with cystic fibrosis. Lancet. 1999;354(9190):1591-1593.

14. Egan TM, Detterbeck FC, Mill MR, et al. Long term results of lung transplantation for cystic fibrosis. Eur J Cardiothorac Surg. 2002;22(4):602-609.

15. Venuta F, Quattrucci S, Rendina EA, et al. Improved results with lung transplantation for cystic fibrosis: a 6-year experience. Interact Cardiovasc Thorac Surg. 2004;3(1):21-24.

16. Quattrucci S, Rolla M, Cimino G, et al. Lung transplantation for cystic fibrosis: 6-year follow-up. J Cyst Fibros. 2005;4(2):107-114.

17. Liou TG, Adler FR, Cahill BC, et al. Survival effect of lung transplantation among patients with cystic fibrosis. JAMA. 2001;286(21):2683-2689.

18. Liou TG, Adler FR, FitzSimmons SC, Cahill BC, Hibbs JR, Marshall BC. Predictive 5-year survivorship model of cystic fibrosis. Am J Epidemiol. 2001;153(4):345-352.

19. Waltz DA, Boucek MM, Edwards LB, et al. Registry of the International Society for Heart and Lung Transplantation: ninth official pediatric lung and heart-lung transplantation report-2006. J Heart Lung Transplant. 2006;25(8):904-911.

20. Waiting list candidates. United Network for Organ Sharing. http://www.unos.org. Accessed November 17, 2008.

21. Data. Organ Procurement and Transplantation Network. http://www.optn.org/data. Accessed November 17, 2008.

22. Orens JB, Estenne M, Arcasoy S, 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):745-755.

23. Drug development pipeline. Cystic Fibrosis Foundation. http://www.cff.org/treatments/Pipeline. Updated November 11, 2008. Accessed November 17, 2008.

24. Wise BV, King KE, Rook AH, Mogayzel PJ Jr. Extracorporeal photopheresis in the treatment of persistent rejection in a pediatric lung transplant recipient. Prog Transplant. 2003;13(1):61-64.

Ingrid M. Pitts is physician assistant in internal medicine and lung transplantation at the University of Florida Hospital in Gainesville, Fla. She indicates no relationships to disclose related to the contents of this article.


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