Lung transplantation and survival in children with cystic fibrosis

Abstract

Background: The effects of lung transplantation on the survival and quality of life in children with cystic fibrosis are uncertain.

Methods: We used data from the U.S. Cystic Fibrosis Foundation Patient Registry and from the Organ Procurement and Transplantation Network to identify children with cystic fibrosis who were on the waiting list for lung transplantation during the period from 1992 through 2002. We performed proportional-hazards survival modeling, using multiple clinically relevant covariates that were available before the children were on the waiting list and the interactions of these covariates with lung transplantation as a time-dependent covariate. The data were insufficient in quality and quantity for a retrospective quality-of-life analysis.

Results: A total of 248 of the 514 children on the waiting list underwent lung transplantation in the United States during the period from 1992 through 2002. Proportional-hazards modeling identified four variables besides transplantation that were associated with changes in survival. Burkholderia cepacia infection was associated with a trend toward decreased survival, regardless of whether the patient underwent transplantation [corrected]. A diagnosis of diabetes before the patient was placed on the waiting list decreased survival while the patient was on the waiting list but did not decrease survival after transplantation, whereas older age did not affect waiting-list survival but decreased post-transplantation survival. Staphylococcus aureus infection increased waiting-list survival but decreased post-transplantation survival. Using age, diabetes status, and S. aureus infection status as covariates, we estimated the effect of transplantation on survival for each patient group, expressed as a hazard factor of less than 1 for a benefit and more than 1 for a risk of harm. Five patients had a significant estimated benefit, 283 patients had a significant risk of harm, 102 patients had an insignificant benefit, and 124 patients had an insignificant risk of harm associated with lung transplantation [corrected].

Conclusions: Our analyses estimated clearly improved survival for only 5 of 514 patients on the waiting list for lung transplantation. Prolongation of life by means of lung transplantation should not be expected in children with cystic fibrosis. A prospective, randomized trial is needed to clarify whether and when patients derive a survival and quality-of-life benefit from lung transplantation.

Figure 1. Survival after Lung Transplantation among 248 Children with Cystic Fibrosis Who Were Younger than 18 Years of Age

The Kaplan–Meier curve (solid black line) is shown along with the upper and lower 95% confidence limits (dashed blue lines). The median survival of these patients was 2.84 years (1037 days). The upper confidence limit shown here roughly matches the post-transplantation Kaplan–Meier survival curve in the report by Aurora et al. The rate of survival at 5 years was 32.9% — somewhat less than the 46.9% reported by the Organ Procurement and Transplantation Network for all recipients of lung transplants for cystic fibrosis.

Figure 2. Estimated Hazard Factors Due to Lung Transplantation

Panel A shows the estimated hazard factors due to lung transplantation calculated for each of the 514 patients in the study, plotted as a function of age. Blue symbols denote the lack of power to determine a significant risk of harm or benefit from transplantation. Red symbols denote a significant risk of harm, and orange symbols a significant benefit. Patients are grouped according to four curves that correspond to the presence of either, both, or neither of the binary variables (S. aureus infection and diabetes). The variable of B. cepacia infection does not interact with transplantation. The value of each hazard factor and the level of significance of each factor within each group at both extremes of age, where the data are sparse, should be viewed with caution, since they may have been the result of overextrapolation of the data. Unfortunately, all five of the patients with an apparently significant decrease in hazard factors (orange symbols) were included in this uncertain category. Panel B shows the estimated hazard factors due to lung transplantation for the 248 patients who underwent the procedure during the study period. These hazard factors are plotted as a function of age. Blue symbols denote the lack of power to determine a significant risk of harm or a significant benefit from transplantation. Red symbols denote a significant risk of harm, and orange symbols denote a significant benefit. A significant decrease in the hazard factor (orange symbol) is apparent for only one patient.

Figure 3. Estimated Hazard Factors for the 514 Patients in the Study According to Clinical Status

Panel A shows the estimated hazard factors calculated as a function of the percent of the predicted value for forced expiratory volume in 1 second, but the data have been arranged as a series of nine scatter plots in order to identify strata. Panel B shows the estimated hazard factors as a function of the 5-year predicted survival probability, expressed as the percent likelihood of survival for 5 years after the date of the last clinic visit before placement on the waiting list. The data are arranged as a series of nine scatter plots in order to identify 5-year predicted survival strata. The hazard factor has no relationship with the 5-year predicted survival (P = 0.87), but it decreases significantly with the FEV₁% (P<0.001). Patients with higher lung function appeared to have less harmful outcomes from lung transplantation, perhaps because of a significant decrease in the FEV₁% with age. Neither FEV₁% nor the 5-year predicted survival probability is helpful for selecting patients who are likely to have a benefit from lung transplantation from among children with cystic fibrosis who have already been selected for the waiting list.