Longevity of Patients With Cystic Fibrosis in 2000 to 2010 and Beyond: Survival Analysis of the Cystic Fibrosis Foundation Patient Registry

Context Cystic fibrosis (CF) is a life-shortening disease, but care has improved. An updated assessment of survival is important for patients and their families and to plan for the health care needs of an increasing number of patients with CF living to adulthood. Contribution The survival of patients with CF enrolled in a national registry increased between 2000 and 2010. Conservative estimates assuming no further improvements suggest that median survival of a patient born and diagnosed in 2010 would be about 39 years. Implication The prognosis of patients with CF has improved, and more of these patients can be expected to need adult care. The Editors Cystic fibrosis (CF) is a heritable, life-shortening disease in which dysfunction of the CF transmembrane conductance regulator (CFTR) epithelial chloride channel dehydrates secretions in the airways, the pancreatic ducts, and elsewhere in the body, causing progressive organ damage (1). In 1966, the Cystic Fibrosis Foundation Patient Registry (CFFPR) was established to track the natural history of the disease, the effect of treatments, and patient health status and to design clinical trials. Registry data have been used to describe survival in CF and the role of specific clinical features in outcomes (25). Approximately 30000 persons in the United States have CF (2), and slightly more than 26000 living persons were represented in the CFFPR in 2010. In the earliest years of the CFFPR, persons with CF did not live to attend elementary school (6). By 2010, almost half of the patients in the registry were aged 18 years or older (6, 7). Advances in pulmonary and nutritional therapies continue to extend the life span of patients with CF. Daily regimens include airway clearance therapy; inhaled mucoactive agents and antibiotics; and a high-calorie, high-fat diet (8, 9). Early identification and management of CF-related diabetes (CFRD) has also been emphasized as a standard of care (10). In addition, universal newborn screening for CF, which has been linked to overall improved health by enabling earlier initiation of treatment (11), was instituted in all 50 states by 2009. Of persons diagnosed in 2010, 57.5% were diagnosed by newborn screening compared with only 8.0% of those diagnosed in 2000 (12). As new therapies emerge and patients with CF live longer, estimating survival is essential to providing an accurate prognosis to parents of newly diagnosed infants. Understandably, parents of children diagnosed with the disease want to provide the best possible care for their child and seek to understand what their child's future will hold (13). Because adults with CF are increasingly apt to pursue life-defining activities, such as marriage, parenthood, higher education, and employment (7, 14), parents may also need to reassess their supportive roles, such as during the period of transition from pediatric to adult care (15). Updated survival estimates will also inform the medical needs of an expanding population of adults with CF (16, 17). Decades of exposure to aminoglycosides are likely to result in increased vestibular (18) and renal dysfunction (19) in the older CF patient population. The prevalence of microvascular complications from CFRD (microalbuminuria, peripheral neuropathy, and retinopathy) increases with the duration of CFRD and should therefore inform screening efforts in older adults (20). Clinicians must also remain vigilant for depression and anxiety (21) among aging patients with CF. Additional unanticipated complications may emerge as the CF patient population continues to age. Recent evaluations of survival in the United Kingdom suggest that children diagnosed with CF since 2000 can anticipate a median survival greater than 50 years (22). Our objective in this study was to characterize survival in the United States between 2000 and 2010 in order to project survival for children born and diagnosed with CF in 2010 and thereby improve the clarity of prognostic dialogue and inform adult care needs. Methods The CFFPR is an institutional review boardapproved observational study at 110 Cystic Fibrosis Foundationaccredited care centers, encompassing more than 260 adult, pediatric, and affiliate programs. Data on patients with CF who have provided consent are collected through a secure Web-based portal. Findings on clinical presentation (such as respiratory symptoms, failure to thrive, and positive newborn screening result confirmed as CF); age at diagnosis; and encounter-based measures of nutritional status, pulmonary function, respiratory cultures, prescribed therapies, and CF-related complications are collected. Our analyses used data from patients in the CFFPR between 1 January 2000 and 31 December 2010 with a confirmed diagnosis of CF based on genotype and phenotype (including sweat chloride, pulmonary function, pancreatic status, and respiratory microbiology) (23). We sought to describe survival between 2000 and 2010, with analysis of mortality according to age, age at diagnosis, gender, race or ethnicity, F508del mutation status, and calendar year, and to project survival of children born and diagnosed with CF in 2010. Statistical Analysis We assessed trends in mortality between 2000 and 2010 by using multivariable Cox proportional hazards models. Calendar year was included as a time-dependent covariate, both as a continuous variable to estimate the rate of change over the decade and as a categorical indicator variable to estimate the rate relative to the year 2000. The time scale in the Cox proportional hazards models was age, with left truncation at entry into the registry or the year 2000, whichever occurred later. We adjusted for gender, race or ethnicity, F508del mutation status, presence of symptoms at diagnosis, and age at diagnosis (24, 25) because these patient characteristics are known at diagnosis (time-independent), are not modifiable by clinical care, and have been shown to be important predictors of survival in CF (24, 25). Therefore, these factors will be most relevant to clinicians who are providing information on prognosis to parents of children with the disease. We adjusted for F508del mutation status because it is an important predictor of survival (26) and its distribution in the CFFPR decreased during the study period. Furthermore, the F508del mutation accounts for approximately 70% of abnormal CFTR alleles, and approximately half of persons with CF are homozygous for this mutation (27). We estimated absolute annual mortality as a function of age, gender, and F508del mutation status for the period from 2000 to 2010 by smoothing age-specific rates with a triangular kernel with a radius of 5 years. Further details on the Cox proportional hazards models, the smoothed estimate of mortality, and subgroup analyses can be found in Appendix 1. We projected survival of children born and diagnosed with CF in 2010 because most future diagnoses will be made early in life due to universal newborn screening. Diagnoses made beyond infancy will probably be in persons with residual CFTR function and a milder phenotype. We present overall results and those stratified by gender and F508del mutation status using the mortality hazards estimated with data from 2000 to 2010 (additional information is provided in Appendix 2). We derived projections assuming that mortality does not change from the rate observed in 2010, mortality decreases at the same rate observed between 2000 and 2010 (1.8%), and mortality decreases at half the rate observed between 2000 and 2010 (0.9%). Institutional review board approval to conduct these analyses was obtained from the Dartmouth Committee for the Protection of Human Subjects. We used R, version 2.15.1, for the analyses, specifically the libraries survival and quantreg. Role of the Funding Source This project was funded by the Cystic Fibrosis Foundation. The funding source had no role in the design, conduct, or analysis of the study but provided access to the CFFPR data and contributed to the interpretation of the findings and the manuscript. Results Table 1 shows characteristics of all 34547 unique patients in the CFFPR from 2000 to 2010. Of these, we excluded patients with missing genotype data (11.9%) and those with missing data on gender, age at diagnosis, or age at entry into the registry (0.4%) from further analyses. Fewer than 4000 individuals (approximately 2.0% per year) were lost to follow-up, with no death date recorded. Between 2000 and 2010, the median age of the cohort increased from 14.3 to 16.7 years and the proportion of patients aged 18 years or older increased from 39% to 48%. Among newly diagnosed patients (that is, those with incident disease), the median age at diagnosis decreased from 6 months in 2000 to 1 month in 2010. The proportion of persons in the CFFPR who were homozygous for the F508del mutation decreased from 51% to 48%. Forty-two percent of patients entering the CFFPR in 2000 were homozygous for the F508del mutation compared with 36% of those entering in 2010. Table 1. Characteristics of Patients in the Cystic Fibrosis Foundation Patient Registry Mortality rate ratios from 2000 to 2010 with respect to calendar year, age at diagnosis, presentation at diagnosis, race or ethnicity, gender, and F508del mutation status are shown in Table 2. Mortality decreased with increasing age at diagnosis; for example, patients diagnosed between ages 5 and 9 years had a 21% (95% CI, 9% to 31%) lower adjusted risk for death than those diagnosed before age 1 year. Males had a 19% (CI, 13% to 24%) lower adjusted risk for death than females. Compared with patients who were homozygous for the F508del mutation, those with 1 copy of the mutation and those with no copies had a 14% (CI, 7% to 20%) and 25% (CI, 15% to 34%) lower adjusted risk for death, respectively. As reported in Table 2, the adjusted hazard ratio for the 10-year change in calendar year (2000 to 2010) was 0.83 (CI, 0.75 to 0.93), which equates to a 17%