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

Demographics

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 ofthese patients would have been two years had they not received a transplant. In comparison, 63% of the posttransplantation patientswere 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.