Effects of gender and age at diagnosis on disease progression in long-term survivors of cystic fibrosis

Abstract

Rationale: Long-term survivors of cystic fibrosis (CF) (age > 40 yr) are a growing population comprising both patients diagnosed with classic manifestations in childhood, and nonclassic phenotypes typically diagnosed as adults. Little is known concerning disease progression and outcomes in these cohorts.

Objectives: Examine effects of age at diagnosis and gender on disease progression, setting of care, response to treatment, and mortality in long-term survivors of CF.

Methods: Retrospective analysis of the Colorado CF Database (1992-2008), CF Foundation Registry (1992-2007), and Multiple Cause of Death Index (1992-2005).

Measurements and main results: Patients with CF diagnosed in childhood and who survive to age 40 years have more severe CFTR genotypes and phenotypes compared with adult-diagnosed patients. However, past the age of 40 years the rate of FEV(1) decline and death from respiratory complications were not different between these cohorts. Compared with males, childhood-diagnosed females were less likely to reach age 40 years, experienced faster FEV(1) declines, and no survival advantage. Females comprised the majority of adult-diagnosed patients, and demonstrated equal FEV(1) decline and longer survival than males, despite a later age at diagnosis. Most adult-diagnosed patients were not followed at CF centers, and with increasing age a smaller percentage of CF deaths appeared in the Cystic Fibrosis Foundation Registry. However, newly diagnosed adults demonstrated sustained FEV(1) improvement in response to CF center care.

Conclusions: For patients with CF older than 40 years, the adult diagnosis correlates with delayed but equally severe pulmonary disease. A gender-associated disadvantage remains for females diagnosed in childhood, but is not present for adult-diagnosed females.

Figure 1.

Age at diagnosis and greatest known age of long-term survivors from the Colorado and Cystic Fibrosis Foundation (CFF) Registry databases. (A) Patients from the Colorado database diagnosed at 10 years or younger were designated as childhood diagnosis (solid circles, CD) and were compared with patients diagnosed at age 18 years or greater, designated as adult diagnosis (open circles, AD). (B) The greatest known age of patients shown in (A) from the Colorado database in the CD cohort was significantly less than that of the AD cohort (*P < 0.001). (C) Patients from the CFF Registry database diagnosed at 10 years or younger (solid circles, CD) were compared with patients diagnosed at age 18 years or greater (open circles, AD). (D) The greatest known age of patients shown in (C) from the CFF Registry database in the CD cohort was significantly less than that of the AD cohort (*P < 0.05).

Figure 2.

Decline in lung function of childhood-diagnosed (CD) and adult-diagnosed (AD) patients older than 40 years was not different. FEV₁ values from all clinic visits captured in the Cystic Fibrosis Foundation (CFF) Registry database for patients over 40 years of age were analyzed. Although AD patients (dotted line) have a significantly higher FEV₁ at age 40 years compared with CD patients (solid line), the rate of FEV₁ decline from age 40 to 60 years was not different between the two cohorts.

Figure 3.

Survival analysis of patients with cystic fibrosis (CF) more than 40 years of age. (A) For patients included in the Colorado database, adult-diagnosed (AD) patients (dashed line) demonstrated a median survival 25.2 years greater than that of childhood-diagnosed (CD) patients (solid line). (B) For patients included in the Cystic Fibrosis Foundation (CFF) Registry, AD patients (dashed line) demonstrated a median survival 14.7 years greater than that of CD patients (solid line).

Figure 4.

The adult diagnosis of cystic fibrosis (CF) occurs with greater frequency and at an older age in women. (A) In the Colorado database, the majority (53.6%) of childhood-diagnosed (CD) patients over 40 years of age were men (solid column), whereas the majority (72.5%) of adult-diagnosed (AD) patients over 40 years of age were women (open column). (B) In the Cystic Fibrosis Foundation (CFF) Registry database, the same pattern was observed, with 60.6% of CD patients over 40 years of age being male (solid column), whereas 54.1% of AD patients over 40 years of age were women (open column). (C) In the Colorado database, the age at diagnosis was 5.8 years older in females (open circles) compared with males (solid circles) (p = NS). (D) In the CFF Registry, females (open circles) were 3.5 years older at the age at diagnosis (*P = 0.0014).

Figure 5.

Gender-dependent decline in lung function of patients with cystic fibrosis (CF) older than 40 years. (A) Women in the childhood diagnosis (CD) cohort (dashed line) had a higher FEV₁ at age 40 years than did CD men (solid line) but demonstrated a greater rate of decline than men (*P ≤ 0.034). (B) Women in the adult diagnosis (AD) cohort (dashed line) did not have a significantly greater FEV₁ and demonstrated a rate of decline in FEV₁ not different from that of AD men (solid line).

Figure 6.

Effect of gender on survival of patients with cystic fibrosis (CF) who are more than 40 years of age. (A) For childhood-diagnosed long-term survivors in the Colorado database no difference was appreciated between male (solid line) and female (dashed line) survival. (B) For childhood-diagnosed long-term survivors in the Cystic Fibrosis Foundation (CFF) Registry database, male (solid line) survival exceeded female (dashed line) survival by 2.4 years (not significant). (C) For adult-diagnosed long-term survivors in the Colorado database, female (dashed line) survival exceeded male (solid line) by 13.5 years. (D) For adult-diagnosed long-term survivors in the CFF Registry database, female (dashed line) survival exceeded male (solid line) survival by 9.2 years.

Figure 7.

Adult-diagnosed (AD) patients are less likely to receive care at a cystic fibrosis (CF) care center. The percentage of patients in the Colorado database found to be entered in the Cystic Fibrosis Foundation (CFF) Registry was plotted against the six most recent years each subject was eligible for entry into the CFF Registry. During this time span, on average 60% of CD patients (open circles) were seen at a CF care center during a given year, compared with 41.7% of AD patients (closed circles) (P < 0.001 by two-way analysis of variance).

Figure 8.

Long-term survivors are less likely to receive care at a cystic fibrosis (CF) center at the time of death. (A) Deaths recorded in the Cystic Fibrosis Foundation (CFF) Registry (open columns) were compared with the number of CF-related deaths in the CDC Mortality Multiple Cause-of-Death (MCOD) Public Use Record (CDC, solid columns). From 1 to 14 years of age, there was no significant difference between the databases. However, significantly fewer infants (age, <1 yr) and patients older than 14 years were entered into the CFF Registry (columns represent means ± SEM; *P < 0.05). (B) Percentage of CF-related deaths not captured in the CFF Registry. The inverse ratio of deaths recorded in the CFF Registry to CF-related deaths in the MCOD is plotted for each age interval (columns represent means ± SEM; P < 0.05). (C) Effect of gender on the percentage of CF-related deaths not captured in the CFF Registry. No significant difference was present between males and females over all ages, or in the subcohort greater than 45 years of age.

Figure 9.

Response to cystic fibrosis (CF) center care by newly diagnosed adults. (A) Response to treatment was assessed in adult-diagnosed patients with CF who established CF center care in the Colorado database (open circles) or in the Cystic Fibrosis Foundation (CFF) Registry (solid squares) with a minimum of 1 year of follow-up visits. The best FEV₁ for each subsequent 12-month period was compared with the FEV₁ measured at the initiation of standard CF center care. The mean change in percent predicted FEV₁ (±SEM) is depicted. For both cohorts, maximal improvement was observed between 1 and 2 years, but lung function remained improved over baseline for the entire 4-year period. The effect of the initial introduction of CF center care can be appreciated in comparison with the observed annual rate of decline for the adult-diagnosed CF population (more than 40 yr of age) as a whole in the CFF Registry (dotted line). (B) Responses of males (solid triangles) and females (open triangles) from the CFF Registry cohort were both significantly improved over baseline, but the difference between the genders was not significant.

Figure 10.

Cause of death analysis of patients in the Cystic Fibrosis Foundation (CFF) Registry whose greatest age exceeded 40 years. Deceased patients with CF in the childhood diagnosis (CD, left) and adult diagnosis (AD, right) cohorts were found to have frequencies for major causes of death that were not different. Specifically, 87% of CD patients died of respiratory or transplantation-related complications, compared with 85% of AD patients.