Epidemiologic Study Of Cystic Fibrosis Research Articles

Epidemiologic Study of Cystic Fibrosis: 25 years of observational research.

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.

Lung function changes before and after pulmonary exacerbation antimicrobial treatment in cystic fibrosis

In cystic fibrosis, observation of a lung function drop (as percent predicted forced expiratory volume in 1 s [FEV1 ]; ppFEV1 ) frequently precedes pulmonary exacerbation (PEx) diagnosis. Recovery of ppFEV1 to a previous "baseline" is commonly used to assess antimicrobial treatment response. However, not all diagnosed PEx are associated with a ppFEV1 drop, and it is unclear whether these are a different type of PEx from those associated with a ppFEV1 drop. We analyzed pre- and posttreatment ppFEV1 for PEx recorded in the Epidemiologic Study of Cystic Fibrosis from 2003 through 2005. Baseline, pretreatment, and follow-up ppFEV1 were the best recorded within 12-months pre-PEx, the lowest recorded -30 to +3 days of treatment, and the best recorded during 6-month follow-up, respectively. Logistic regression models for return of ppFEV1 to baseline during follow-up were developed separately for PEx with ≥10%, <10%, and no ppFEV1 drop before treatment. Of 15 147 PEx, 10 166 (67.1%), 3479 (23.0%), and 1502 (9.9%) presented with a≥10%, <10%, or no ppFEV1 drop at diagnosis, respectively. 19.5%, 35.2%, and 65.6% of PEx, respectively, had follow-up ppFEV1 equal to or exceeding baseline; overall 27.7% of all PEx treatments resulted in complete recovery of baseline ppFEV1 . Significant predictors of ppFEV1 recovery at follow-up were younger patient age, absence of Aspergillus, lower baseline ppFEV1 , fewer visits during the baseline, lower frequency of prior-year PEx, shorter elapsed time from baseline measure to treatment, smaller relative ppFEV1 drop before treatment, and non intravenous(ie, oral or inhaled antibiotic) treatment. PEx with ≥10%, <10%, and no ppFEV1 drop before treatment had only modest differences in covariate odds ratios associated with complete ppFEV1 recovery. Among the 10% of PEx presenting with no apparent ppFEV1 drop, more than one-third resulted in a decreased ppFEV1 during follow-up. Risk factors for this outcome were the same as those associated with lack of ppFEV1 recovery among PEx with pretreatment ppFEV1 drops. These results suggest that inherent FEV1 variability, baseline and follow-up sampling methodologies, ppFEV1 regression to the mean, and underlying lung disease progression complicate this approach for assessing effects of PEx and treatment response.

Association of High-Dose Ibuprofen Use, Lung Function Decline, and Long-Term Survival in Children with Cystic Fibrosis.

Cystic fibrosis deaths result primarily from lung function loss, so chronic respiratory therapies, intended to preserve lung function, are cornerstones of cystic fibrosis care. Although treatment-associated reduction in rate of lung function loss should ultimately improve cystic fibrosis survival, no such relationship has been described for any chronic cystic fibrosis therapy. In part, this is because the ages of most rapid lung function decline-early adolescence-precede the median age of cystic fibrosis deaths by more than a decade. To study associations of high-dose ibuprofen treatment with the rate of forced expiratory volume in 1 second decline and mortality among children followed in the Epidemiologic Study of Cystic Fibrosis and subsequently in the U.S. Cystic Fibrosis Foundation Patient Registry. We performed a matched cohort study using data from Epidemiologic Study of Cystic Fibrosis. Exposure was defined as high-dose ibuprofen use reported at ≥80% of encounters over 2 years. Unexposed children were matched to exposed children 5:1 using propensity scores on the basis of demographic, clinical, and treatment covariates. The rate of decline of percent predicted forced expiratory volume in 1 second during the 2-year follow-up period was estimated by mixed-effects modeling with random slopes and intercepts. Survival over 16 follow-up years in the U.S. Cystic Fibrosis Foundation Patient Registry was compared between treatment groups by using proportional hazards modeling controlling for matching and covariates. We included 775 high-dose ibuprofen users and 3,665 nonusers who were well matched on demographic, clinical, and treatment variables. High-dose ibuprofen users declined on average 1.10 percent predicted forced expiratory volume in 1 second/yr (95% confidence interval; 0.51, 1.69) during the 2-year treatment period, whereas nonusers declined at a rate of 1.76% percent predicted forced expiratory volume in 1 second/yr (95% confidence interval; 1.48, 2.04) during the corresponding 2-year period, a 37.5% slower decline among users compared with nonusers (95% confidence interval; 0.4%, 71.3%; P = 0.046). The users had better subsequent survival (P < 0.001): the unadjusted and adjusted hazard ratios for mortality (high-dose ibuprofen/non-high-dose ibuprofen) (95% confidence interval) were 0.75 (0.64, 0.87) and 0.82 (0.69, 0.96). In a propensity-score matched cohort study of children with cystic fibrosis, we observed an association between high-dose ibuprofen use and both slower lung function decline and improved long-term survival. These results are consistent with the hypothesis that treatment-associated reduction of lung function decline in children with cystic fibrosis leads to improved survival.

Treatment Setting and Outcomes of Cystic Fibrosis Pulmonary Exacerbations.

There are important gaps in knowledge of the optimal treatment of cystic fibrosis pulmonary exacerbations. Previous observational studies comparing inpatient with outpatient treatment have suffered from methodologic weaknesses, especially indication bias. We analyzed data from the Epidemiologic Study of Cystic Fibrosis using techniques to control for indication bias to determine whether there is an advantage to inpatient treatment of cystic fibrosis pulmonary exacerbations. We identified typical pulmonary exacerbations in patients ages 6 years and older during the 3-year observation period ending in 2005. In our primary analysis, we used the instrumental variables method, implemented using two-stage least squares regression, to evaluate the effect of the proportion of total time that intravenous treatment was administered on an inpatient (versus outpatient) basis on the likelihood of return of percent predicted forced expiratory volume in 1 second to greater than or equal to 90% of baseline post-treatment. We also evaluated two other indicators of treatment setting, three other measures of treatment response, and two alternative modeling techniques, and we also looked for differences between children and adults. Our final analysis included 4,497 pulmonary exacerbations in 2,773 individual patients at 75 sites. We calculated the mean proportion of intravenous treatment time that was provided in the hospital setting at each site. The median across sites was 0.581 (interquartile range, 0.396-0.753). The median treatment success rate across sites was 74.2% (interquartile range, 67.9 to 79.2%). Univariate analysis and two-stage least squares models showed a positive relationship between treatment success and proportion of inpatient treatment days. Our primary model revealed an absolute increase of 9.08% (95% confidence interval, 2.55-15.61; P = 0.006) in the achievement of a return of percent predicted forced expiratory volume in 1 second to greater than or equal to 90% of baseline comparing complete inpatient treatment with no inpatient treatment. Treatment response was not related to duration of intravenous therapy. Similar results were found for all our modeling techniques and outcomes. Patients with cystic fibrosis treated at sites with more reliance on inpatient treatment were more likely to achieve successful forced expiratory volume in 1 second recovery. There was no relationship between treatment duration and recovery of forced expiratory volume in 1 second.

Cystic fibrosis clinical characteristics associated with dornase alfa treatment regimen change.

When the chronic respiratory therapy dornase alfa was made commercially available for cystic fibrosis (CF) more than 20 years ago, two regimens were approved: 2.5 mg inhaled once daily (QD) or twice daily (BID). In the intervening years, there has been little guidance as to when to use each regimen. We have studied clinical practice patterns captured in the Epidemiologic Study of CF (ESCF) during the decade following dornase alfa approval (1994-2005) to better understand clinical characteristics associated with QD versus BID dornase alfa use. Methods We studied the characteristics of ESCF patients who received either dornase alfa regimen for at least 12 months and who were then switched to the alternate regimen for at least 6 months and who had adequate data available around the time of the switch. Average lung function and weight-for-age (WFA) z-scores, numbers of intravenous (IV) antibiotic-treated pulmonary exacerbations, and prevalence of signs and symptoms were determined for 6-month periods capturing the beginning (FIRST) and the end (LAST) of the initial regimen, the 6 months preceding the final 6 months of the initial regimen (PRIOR), and the beginning of the second regimen (POST). Changes in values from FIRST to LAST, PRIOR to LAST, and LAST to POST were studied to better understand clinical scenarios associated with decisions to change regimens. A total of 1342 QD and 574 BID regimens were studied with median durations of 3.19 and 2.09 years, respectively. On average, patients beginning BID regimens had worse lung function and a greater number of pulmonary exacerbations treated with IV antibiotics than those beginning QD regimens. However, by the time of regimen switch, patients switching from QD to BID dornase alfa had experienced substantial deterioration with respect to pulmonary exacerbations and signs and symptoms, whereas patients switching from BID to QD had not. Interestingly, incidence of IV-treated pulmonary exacerbations and signs and symptom prevalence decreased for both populations after regimen switch. We have studied populations of patients with CF receiving dornase alfa who were switched between regimens to characterize clinical course. Our results suggest that the most common clinical attribute associated with switching from QD to BID dornase alfa was a marked deterioration in stability characterized by increased incidence and frequency of pulmonary exacerbation. For this population, deterioration in lung function did not appear to be a driver for this switch. In contrast, patients receiving BID dornase alfa who were ultimately switched to QD appeared to be clinically stable, on average, suggesting that treatment burden and cost may have been drivers of the decision to switch regimens.

Do cystic fibrosis centres with the lowest FEV1 still use the least amount of intravenous antibiotics? A registry-based comparison of intravenous antibiotic use among adult CF centres in the UK

BackgroundThe Epidemiologic Study of Cystic Fibrosis using 1995–1996 and 2003–2005 data found that CF centres with lowest FEV1 tended to use fewer intravenous antibiotics. We repeated the analyses using 2013–2014 UK CF registry data to determine if this was still the case. MethodsAnalysing data for 2013 and 2014 separately, 28 adult CF centres were ranked according to median % age-adjusted FEV1. The top 7 centres were placed in the ‘upper quarter’ (best FEV1), the bottom 7 centres in ‘lower quarter’ (lowest FEV1), and the rest in ‘middle half’. IV use was stratified according to %FEV1, then compared between the three groups. ResultsCentres in the ‘upper quarter’ and ‘middle half’ used significantly more IV antibiotics compared to centres in the ‘lower quarter’ (van Elteren test P-value<0.001). Regression analyses showed that people with CF attending centres in the ‘upper quarter’ or ‘middle half’ are 30–50% more likely to receive at least one IV course per year compared to people attending centres in the ‘lower quarter’. ConclusionsCF centres with lowest FEV1 are still distinguished by lower use of intravenous antibiotics.

Comparison of FEV1 reference equations for evaluating a cystic fibrosis therapeutic intervention.

The Global Lung Function Initiative (GLI, 2012) developed reference equations for forced expiratory volume in 1 s (FEV1 ). Previous equations were developed by groups led by Knudson (1983), Wang (1993), Hankinson (1999), and Stanojevic (2008).1,2,4,6 We assessed how different prediction equations affect the conclusions from a therapeutic intervention study that evaluated the rate of percent predicted FEV1 (ppFEV1 ) decline. Using data from the Epidemiologic Study of cystic fibrosis (CF), we re-analyzed our previous study evaluating the relationship of dornase alfa (DA) use with ppFEV1 using the Knudson, Wang & Hankinson, Stanojevic, and GLI equations. The change in intercept and change in slope of ppFEV1 from a 2-year pre-index period and 2-year post-index period were compared between the treated (N = 2483) and comparator groups (N = 6992, from 4110 unique patients). Change in intercept for the comparator group was similar across equations except that Wang & Hankinson values were more negative. The difference in change in intercept between the DA and comparator groups ranged from 3.38 to 4.02% predicted. The change in slope for the comparator group ranged from -0.58 to +0.30 ppFEV1 /year, but the difference in change in slope between the DA and comparator groups was in a narrower range from +0.53 to +0.89 ppFEV1 /year. Although individual patient results are impacted by the choice of reference equations, the study conclusions from this evaluation of a therapeutic intervention were minimally affected. GLI equations are recommended for future studies, but prior results based on other equations should be accepted as reliable.

Relationship of Antibiotic Treatment to Recovery after Acute FEV1 Decline in Children with Cystic Fibrosis.

Children with cystic fibrosis often experience acute declines in lung function. We previously showed that such declines are not always treated with antibiotics, but we did not assess whether treatment improves the likelihood of recovery. To determine whether new antibiotic treatment was associated with recovery from acute FEV1 decline. We studied episodes of FEV1 decline (≥10% from baseline) in the Epidemiologic Study of Cystic Fibrosis. Treatments were hospitalization, home intravenous antibiotic, new inhaled oral quinolone, or other oral antibiotic. We used logistic regression to evaluate whether treatment was associated with recovery to baseline or near baseline. Logistic regression of 9,875 patients showed that new antibiotic treatment was associated with an increased likelihood of recovery to 90% of baseline (P < 0.001), especially for hospitalization compared with no new antibiotic (odds ratio [OR], 2.79; 95% confidence interval, 2.41-3.23). All four outpatient treatments were associated with greater likelihood of recovery compared with no treatment (OR, 1.27-1.64). Inpatient treatment was better than outpatient treatment (OR, 1.94; 95% confidence interval, 1.68-2.23). Treatment-type ORs were similar across recovery criteria and levels of baseline lung function. New antibiotic therapy, and especially inpatient treatment, is associated with greater likelihood of recovery after acute decline in FEV1. Benefits extend across all disease stages and are especially important in patients with high lung function, who are at greatest risk for FEV1 decline.

Risk factors for mortality before age 18 years in cystic fibrosis.

Understanding early-life risk factors for childhood death in cystic fibrosis (CF) is important for clinical care, including the identification of effective interventions. Data from the Epidemiologic Study of Cystic Fibrosis (ESCF) collected 1994-2005 were linked with the Cystic Fibrosis Foundation Patient Registry (CFFPR) demographic and mortality data from 2013. Inclusion criteria were ≥1 visit annually at age 3-5 years and ≥1 FEV1 measurement at age 6-8 years. Demographic data, nutritional parameters, pulmonary signs and symptoms, microbiology, and FEV1 were evaluated as risk factors for death before age 18 years. Multivariable Cox proportional hazards regression was used to model the simultaneous effects of risk factors associated with death before age 18 years. Among 5365 patients enrolled in ESCF who met inclusion criteria, 3880 (72%) were linked to the CFFPR. Among these, 191 (5.7%) died before age 18 years; median age at death was 13.4 ± 3.1 years. Multivariable regression showed clubbing, crackles, female sex, unknown CFTR genotype, minority race or ethnicity, Medicaid insurance (a proxy of low socioeconomic status), Pseudomonas aeruginosa on 2 or more cultures, and weight-for-age <50th percentile were significant risk factors for death regardless of inclusion of FEV1 at age 6-8 years in the model. We identified multiple risk factors for childhood death of patients with CF, all of which remained important after incorporating FEV1 at age 6-8 years. Among the factors identified were the presence of clubbing or crackles at age 3-5 years, signs which are not routinely collected in registries.

BMI fails to identify poor nutritional status in stunted children with CF

BackgroundBody mass index (BMI) is currently emphasized for evaluating nutritional status in children with cystic fibrosis (CF). Weight for age (WFA) and height for age (HFA) may get less attention. MethodsData from the Epidemiologic Study of Cystic Fibrosis were used to compare patient WFA, HFA, and BMI percentiles for children age 2 to 18years. ResultsFor children with BMI between the 25th and 50th percentiles, 16.8% had WFA <10th percentile and 26.6% had HFA <10th percentile. ConclusionsBMI fails to identify a substantial proportion of children with CF who have stunting or potentially poor nutritional status as measured by WFA and/or HFA.

Forced Expiratory Volume in 1 Second Variability Helps Identify Patients with Cystic Fibrosis at Risk of Greater Loss of Lung Function

To evaluate several alternative measures of forced expiratory volume in 1 second percent predicted (FEV1 %pred) variability as potential predictors of future FEV1 %pred decline in patients with cystic fibrosis. We included 13,827 patients age ≥6 years from the Epidemiologic Study of Cystic Fibrosis 1994-2002 with ≥4 FEV1 %pred measurements spanning ≥366 days in both a 2-year baseline period and a 2-year follow-up period. We predicted change from best baseline FEV1 %pred to best follow-up FEV1 %pred and change from baseline to best in the second follow-up year by using multivariable regression stratified by 4 lung-disease stages. We assessed 5 measures of variability (some as deviations from the best and some as deviations from the trend line) both alone and after controlling for demographic and clinical factors and for the slope and level of FEV1 %pred. All 5 measures of FEV1 %pred variability were predictive, but the strongest predictor was median deviation from the best FEV1 %pred in the baseline period. The contribution to explanatory power (R(2)) was substantial and exceeded the total contribution of all other factors excluding the FEV1 %pred rate of decline. Adding the other variability measures provided minimal additional value. Median deviation from the best FEV1 %pred is a simple metric that markedly improves prediction of FEV1 %pred decline even after the inclusion of demographic and clinical characteristics and the FEV1 %pred rate of decline. The routine calculation of this variability measure could allow clinicians to better identify patients at risk and therefore in need of increased intervention.

Decline in lung function does not predict future decline in lung function in cystic fibrosis patients.

Despite the attention paid to minimizing lung function decline among cystic fibrosis (CF) patients, the effect of rate of decline on subsequent disease progression is poorly understood. We aimed to describe the rate of decline of FVC, FEV1 , and FEF25-75 and to test the hypothesis that rate of decline of each spirometric variable predicts subsequent rate of decline in that variable and each other variable. Data were from the Epidemiologic Study of CF, an observational study of North American CF patients from 1994 to 2005. For each year of age, patients' best percent predicted FEV1 and associated FVC and FEF25-75, were used to calculate 2-year slopes for each spirometric variable. Pearson correlations were calculated between reference slopes and follow-up slopes up to 8 years later and, for FEV1 , between reference slopes and level (not slope) of lung function up to 5 years later. Twenty six thousand, three hundred and ninety-three patients contributed 427,063 spirometries. Median 2-year slopes of all variables were negative for all ages >6 years and the magnitude varied with age, being greatest among 13-17 year olds, especially for FEF25-75 . There was no correlation (r < 0.10) between reference slopes and subsequent slopes 3-8 years later, either within or across variables. The correlation between 2-year FEV1 slopes and FEV1 level even 5 years later was moderate (0.37-0.49) across disease stage categories. Contrary to our hypothesis, rate of lung function decline did not predict future rate of decline either within or across spirometric variables. In contrast, FEV1 slope did have moderate predictive ability for subsequent FEV1 level. These findings are relevant for clinical care and for clinical trial design.

Early childhood wheezing is associated with lower lung function in cystic fibrosis

To study the association between wheezing in children with cystic fibrosis (CF) and lung function in later life. We used data from the Epidemiologic Study of CF, a longitudinal observational study from 1994 to 2005. Wheezing phenotypes were defined as: no wheezing in the first 6 years of life (NW), transient wheezing (TW; wheezing <3 years old, but no wheezing after 3), late wheezing (LW; wheezing only after age 3 years), and persistent wheezing (PW; wheezing both before and after age 3 years). A linear regression model was developed predicting the best forced expiratory volume in 1 sec (FEV1 ) at age 6 or 7 years (6 to <8) for each wheezing phenotype. A total of 1302 children met the cohort inclusion criteria; 61% of the cohort had wheezing in the first 6 years of life. A history of any wheezing in the first 6 years of life was associated with a significantly lower FEV1 at 6 to <8 years compared to children with NW. The FEV1 of children with NW at age 6 to <8 years was 104% predicted, whereas the mean FEV1 in TW, LW, and PW groups was 98%, 100%, and 96% predicted, respectively (P < 0.05 compared to NW). Childhood wheezing in CF is common and is associated with lower lung function at age 6 to <8 years. Our results identify a clinical feature in early childhood CF associated with lower lung function in later life.

Clinical use of tobramycin inhalation solution (TOBI®) shows sustained improvement in FEV1 in cystic fibrosis

Tobramycin inhalation solution (TIS; TOBI®) has improved forced expiratory volume in 1 sec (FEV1 ) in cystic fibrosis (CF) trials. Using data from the Epidemiologic Study of CF (ESCF), we assessed the change in level and trend of FEV1 % predicted (pred) over a 2-year period associated with initiation of TIS during routine clinical practice. Patients age 8-38 years and in ESCF for ≥2 years before treatment with TIS as a chronic therapy were selected if they remained on therapy for 2 years, defined as being on TIS for at least 3 months per year (C-TIS group). Comparator intervals age 8-38 years used TIS <10% of the time. For each interval, we estimated the level and trend (rate of decline) in FEV1 % pred before and after the index using a piecewise linear mixed-effects model adjusted for potential confounders. During the 2-year pre-index period the C-TIS group (n = 2,534) had a more rapid decline in FEV1 (-2.49% vs. -1.39% pred/year) and a lower FEV1 at index (62.6% vs. 74.7% pred) than the comparator group (N = 17,656 intervals). After starting chronic TIS, the FEV1 trend line over the 2-year post-index period was higher, but the comparator group's FEV1 was essentially unchanged (difference 2.22, P < 0.001). Change in slope was not different between groups (0.06, P = 0.82). Initiating chronic TIS therapy in the routine clinical care of patients with CF was associated with improvement in FEV1 % pred but no change in rate of decline, which means that this benefit was sustained over the 2 years studied.

Standard care versus protocol based therapy for new onset Pseudomonas aeruginosa in cystic fibrosis

The Early Pseudomonal Infection Control (EPIC) randomized trial rigorously evaluated the efficacy of different antibiotic regimens for eradication of newly identified Pseudomonas (Pa) in children with cystic fibrosis (CF). Protocol based therapy in the trial was provided based on culture positivity independent of symptoms. It is unclear whether outcomes observed in the clinical trial were different than those that would have been observed with historical standard of care driven more heavily by respiratory symptoms than culture positivity alone. We hypothesized that the incidence of Pa recurrence and hospitalizations would be significantly reduced among trial participants as compared to historical controls whose standard of care preceded the widespread adoption of tobramycin inhalation solution (TIS) as initial eradication therapy at the time of new isolation of Pa. Eligibility criteria from the trial were used to derive historical controls from the Epidemiologic Study of CF (ESCF) who received standard of care treatment from 1995 to 1998, before widespread availability of TIS. Pa recurrence and hospitalization outcomes were assessed over a 15-month time period. As compared to 100% of the 304 trial participants, only 296/608 (49%) historical controls received antibiotics within an average of 20 weeks after new onset Pa. Pa recurrence occurred among 104/298 (35%) of the trial participants as compared to 295/549 (54%) of historical controls (19% difference, 95% CI: 12%, 26%, P < 0.001). No significant differences in the incidence of hospitalization were observed between cohorts. Protocol-based antimicrobial therapy for newly acquired Pa resulted in a lower rate of Pa recurrence but comparable hospitalization rates as compared to a historical control cohort less aggressively treated with antibiotics for new onset Pa.

Probability of Treatment Following Acute Decline in Lung Function in Children with Cystic Fibrosis is Related to Baseline Pulmonary Function

To determine whether the association between high forced expiratory volume in 1 second (FEV1) and increased rate of decline in FEV1 in children with cystic fibrosis could be due to less frequent intervention after acute declines (sudden decline events) in FEV1. Patients with cystic fibrosis aged 6-17 years enrolled in the Epidemiologic Study of Cystic Fibrosis were assessed for a sudden decline event, defined as a 10% relative decline in FEV1% predicted from an average of 3 consecutive stable baseline spirometries. The likelihood of therapeutic intervention within 14 days before and 56 days after this event was then related to their baseline FEV1% predicted age-specific decile using a logistic regression adjusting for age group (6-12 years, 13-17 years) and presence of Pseudomonas aeruginosa on respiratory culture. A total of 10 888 patients had at least 1 sudden decline event in FEV1. Patients in the highest FEV1 decile were significantly less likely than those in the lowest decile to receive intravenous antibiotics (OR, 0.14; 95% CI, 0.11-0.18; P < .001) or be hospitalized (OR, 0.18; 95% CI, 0.14-0.23; P < .001) following decline. Children and adolescents with high baseline lung function are less likely to receive a therapeutic intervention following an acute decline in FEV1, which may explain their greater rate of FEV1 decline.

Treatment complexity in cystic fibrosis: Trends over time and associations with site-specific outcomes

Patients with cystic fibrosis (CF) have increasing treatment complexity and high treatment burden. We describe trends in treatment complexity and evaluate its relationship with health outcomes. Using Epidemiologic Study of Cystic Fibrosis (ESCF) data, we developed a treatment complexity score (TCS) from 37 chronic therapies and assessed change by age group (6-13, 14-17, and 18+ years) over a three year period. Differences in average site TCS were evaluated by quartiles based on FEV1, BMI, or Treatment Burden score on the Cystic Fibrosis Questionnaire-Revised (CFQ-R). TCS scores were calculated for 7252 individual patients (42% child, 16% adolescent, 43% adult) across 153 sites. In 2003, mean TCS was 11.1 for children, 11.8 for adolescents, and 12.1 for adults. In all 3 age groups, TCS increased over 3 years; the increase in TCS from 2003-2005 for children was 1.25 (95% CI 1.16-1.34), for adolescents 0.77 (0.62-0.93), and for adults 1.20 (1.08-1.31) (all P<0.001 for trend over time). At the site level, there were no significant differences in mean TCS based on FEV1 quartile. Mean TCS was higher in the highest BMI z-score quartile. Across all 3 versions of the CFQ-R, mean TCS was lower at sites in the highest quartiles (lowest burden) for CFQ-R treatment burden scores. Treatment complexity was highest among adults with CF, although over 3 years, we observed a significant increase in treatment complexity in all age groups. Such increases in treatment complexity pose a challenge to patient self-management and adherence. Future research is needed to understand the associations between treatment complexity and subsequent health outcomes to reduce treatment burden and improve disease management.

Pulmonary exacerbations in cystic fibrosis: Young children with characteristic signs and symptoms

A standard definition of pulmonary exacerbation based on signs and symptoms would be useful for categorizing cystic fibrosis (CF) patients and as an outcome measure of therapy. The frequently used definition of treatment with intravenous antibiotics varies with practice patterns. One approach to this problem is to use large data sets which include a patient's signs and symptoms along with their clinician's decision to treat with antibiotics for the diagnosis of pulmonary exacerbation. Previous analysis of such a data set, the Epidemiologic Study of Cystic Fibrosis (ESCF), found that new crackles, increased cough, increased sputum, and weight decline were the four clinical characteristics most strongly influencing providers to treat young CF patients for a pulmonary exacerbation. The objectives of this study were to confirm that these four characteristics influence the decision to treat with antibiotics for a pulmonary exacerbation in young CF patients; to evaluate their implications for future nutritional status and lung function; and to assess the effect of antibiotic treatment on these characteristic signs and symptoms. This was an observational, longitudinal cohort study of clinical care in children <6 years old cared for at sites participating in ESCF. Using data from children not included in the previous ESCF study, we confirmed that these four characteristics were significantly associated with the likelihood of physicians prescribing antibiotics to treat a pulmonary exacerbation. The number of these characteristics present at a single clinic visit before age 6 predicted hospitalization rate over the next year, the weight-for-age z-score, and the forced expiratory volume in 1 sec (FEV1) percent predicted at age 7. Treatment with antibiotics was associated with a greater decrease in the proportion of children with crackles, cough, and Pseudomonas aeruginosa at a follow-up visit within 6 months. New crackles, increased cough, increased sputum, and decline in weight percentile at a single clinic visit increase the risk of future malnutrition, hospitalization, and airflow obstruction in young children with CF. Treatment with antibiotics mitigates some of these signs and symptoms by the first follow-up visit. The presence of these four characteristic signs and symptoms is useful to define pulmonary exacerbations in young children with CF that respond to antibiotic treatment in the short-term and influence long-term prognosis.

Oral, inhaled, and intravenous antibiotic choice for treating pulmonary exacerbations in cystic fibrosis

Patients with cystic fibrosis (CF) experience frequent pulmonary exacerbations (PExs). Clinicians manage these episodes of worsening signs and symptoms in a variety of ways. To characterize the antibiotic management and associated change in lung function following PExs. We used 2003-2005 data from the Epidemiologic Study of Cystic Fibrosis to examine antibiotic treatment and the immediate and long-term lung function change associated with clinician reported PExs. A total of 45,374 PExs were reported in 13,194 unique patients. Most PExs (73%) were treated with oral antibiotics, while 39% were treated IV and 24% were treated with inhaled antibiotics. The likelihood of non-IV versus IV antibiotic treatment was associated with the patient's age, stage of lung disease, and magnitude of lung function drop prior to the PEx. Following treatment, the average improvement in the FEV1 was 3.4 ± 12.2% predicted with a greater (5.1 ± 12.7% predicted) improvement following IV antibiotic treatment than with non-IV treatment (2.0 ± 11.6% predicted). When the best FEV1 from the year before was compared with 180 days following the PEx there was an average fall of 3.8 ± 10.5% predicted with little difference observed between antibiotic treatment routes. Patients with only one exacerbation during the 3-year study had a similar loss of lung function to patients with no reported exacerbations. Clinicians treat the majority of PExs with oral antibiotics, particularly in younger, healthier patients. Pulmonary function improves with antibiotic therapy, however, PExs are associated with lung function deterioration over time.

Risk factors for rate of decline in FEV1 in adults with cystic fibrosis

BackgroundPreviously we assessed risk factors for FEV1 decline in children and adolescents using the Epidemiologic Study of Cystic Fibrosis (J Pediatr 2007;151:134–139); the current study assessed risk factors in adults. MethodsRisk factors for FEV1 decline over 3–5.5years for ages 18–24 and ≥25years were assessed using mixed-model regression. ResultsMean rates of FEV1 decline (% predicted/year) were −1.92 for ages 18-24y (n=2793) and −1.45 for ages ≥25y (n=1368). For the 18-24y group, B. cepacia, pancreatic enzyme use, multidrug-resistant P. aeruginosa, cough, mucoid P. aeruginosa, and female sex predicted greater decline; low baseline FEV1 and sinusitis predicted less decline. For the ≥25y group, only pancreatic enzyme use predicted greater decline; low baseline FEV1 and sinusitis predicted less decline. ConclusionsRisk factors for FEV1 decline in adults <25years are similar to those previously identified in children and adolescents; older adults had few statistically significant risk factors.