Epidemiologic Study of Cystic Fibrosis: 25 years of observational research

Abstract

The Epidemiologic Study of Cystic Fibrosis (ESCF) was a prospective observational study of over 32,000 people with cystic fibrosis (CF) from 250 clinical care sites in North America from 1994 to 2005. Begun as a pharmacovigilance study in connection with the approval of dornase alfa in 1993, ESCF was open to all people with CF treated at any participating site in the United States or Canada. In addition to obtaining safety and effectiveness data on dornase alfa, ESCF collected encounter-based data to characterize the natural history and management of CF with a special focus on lung disease. During the study, 32,178 patients reported at least one encounter, contributing 869,136 encounters, 622,592 pulmonary function tests, 432,896 cultures, and 118,563 pulmonary exacerbations treated with intravenous antibiotics. Although ESCF data collection concluded in 2005, through a collaboration with the U.S. Cystic Fibrosis Foundation Patient Registry, additional follow-up data through 2017 was available for two-thirds of patients. This allowed for updating of CF genotype and survival information. Fifty-six peer-reviewed publications (cited over 3600 times) resulted from this study. In this manuscript we summarize the published ESCF manuscripts in thematic groups with key study findings and brief comments, and speculate on how ESCF findings will inform future data registries and patient care practices.

Keywords: cystic fibrosis; epidemiology; lung function; pulmonary exacerbation.

Figure 1

FIGURE 1Percentage of patients reaching onset of persistent sign/symptom by age. Adapted with permission from Pediatric Pulmonology

Figure 2

Risk factors for mortality before age 18 years. Hazard ratios for two survival models: one that does not include ppFEV1category as a predictor (open circles) and one that includes ppFEV1category as a predictor (filled circles). Adapted with permission from Pediatric Pulmonology.50CFFPR, Cystic Fibrosis Foundation Patient Registry; ppFEV1, percent predicted forced expiratory volume in 1 s

Figure 3

Treatment of PEx. Panel A. Percentage of children and adolescents treated with antibiotics after acute≥10% relative FEV1 drop stratified by ppFEV1 decile and age group. Adapted with permission from the Journal of Pediatrics.40Panel B. Area-proportional diagram of antibiotic treatments of clinician-identified exacerbations by route of administration. Adapted with permission from Pediatric Pulmonology.35Panel C. Mean antibiotic treatment events per patient‐year by IV route (upper panel) and by any route (lower panel). Adapted with permission from the Journal of cystic fibrosis.37Panel D. Documentation and antibiotic (ABX) treatment of PEx identified by Rabin Criteria or by≥15ppFEV1 drop. Odds ratios of treatment are shown for top quartile sites (Q1) versus other quartiles (Q2–Q4). Adapted with permission from Pediatric Pulmonology.44Panel E. Percentage of young children treated with antibiotics by number of Rabin Criteria present. Adapted with permission from Pediatric Pulmonology.34Panel F. Odds ratios for recovery of≥90% of baseline ppFEV1 after PEx for patients receiving in patient (filled circles) or outpatient (open circles) treatment as a function of ppFEV1 drop at diagnosis (upper panel) and Baseline ppFEV1(lower panel). Adapted with permission from the Annals of the American Thoracic Society.49IV, intravenous; PEx, pulmonary exacerbation; ppFEV1, percent predicted forced expiratory volume in 1 s

FIGURE 4

Lung function decline by age and baseline ppFEV1.Panel A. Mean rates of ppFEV1 decline by age group. Overall rates (open circles) and rates stratified by baseline ppFEV1 category (filled circles) adjusted for other risk factors are shown. Adapted with permission from the Journal of Pediatrics and the Journal of CysticFibrosis.14,33Panel B. Average changes in ppFEV1 around age 18years by ppFEV1 category adjusted for other risk factors. Adapted with permission from Pediatric Pulmonology.30ppFEV1, percent predicted forced expiratory volume in 1 s

FIGURE 5

Change in lung function by age. mean, median, and quartile changes in best recorded ppFEV1 from the prior year are shown as a function of age. Bars represent 95% CI. Adapted with permission from the Journal of Cystic Fibrosis. 95% CI, 95% confidence interval; ppFEV1, percent predicted forced expiratory volume in 1 s

FIGURE 6

Prediction of best ppFEV1 in subsequent 2 years after2-year baseline. Contribution to percentage of variance explained(R2) in a regression model of ppFEV1 variability (as measured by median deviation from best ppFEV1; open bars), trendline slope (rate of ppFEV1 decline; gray bars), and all other factors (demographics, clinical factors, and trendline intercept; black bars). Adapted with permission from the Journal of Pediatrics. ppFEV1, percent predicted forced expiratory volume in 1 s

FIGURE 7

Change-point models of ppFEV1 before and after initiation of chronic treatments. Panel A. Change in ppFEV1 among children (upper lines) and adults (lower lines) receiving chronic dornase alfa treatment (DA; solid lines) versus an untreated comparator group (dashed lines). Mean ppFEV1 decline rates (slopes) are shown above lines; differences in intercept between lines are shown with arrows. Adapted with permission from Pediatric Pulmonology.26Panel B. Change in ppFEV1 among children receiving chronic ICS (solid lines) versus an untreated comparator group (dashed lines). Derived from previously published data.17Panel C. Change in ppFEV1 among patients ages 8 to38 years receiving chronic TIS (solid lines) versus an untreated comparator group (dashed lines). Mean ppFEV1 decline rates (slopes) are shown next to lines; differences in intercept between lines are shown with arrows. Derived from previously published data.41ICS, inhaled corticosteroids; ppFEV1, percent predicted forced expiratory volume in 1 s; TIS, tobramycin inhalation solution

FIGURE 8

Survival after initiation of at least 2 years of chronic HDI in children (6–17 years). The 2-year HDI exposure period is shown as a gray box. Survival among patients receiving at least 2years of chronic HDI (N= 775) is represented as a black line and survival among propensity-matched comparator patients (N= 3665 )is shown in gray. Adapted with permission from the Annals of the American Thoracic Society.54HDI, high-dose ibuprofen