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

OBJECTIVE: 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. STUDY DESIGN: 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. RESULTS: 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. CONCLUSIONS: 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.

Sustained Benefit from ivacaftor demonstrated by combining clinical trial and cystic fibrosis patient registry data.

RATIONALE: In clinical trials, patients with cystic fibrosis and a G551D mutation who received ivacaftor experienced improvements in pulmonary and nutritional outcomes. However, whether these improvements reflect a change in disease trajectory cannot be determined without longer-term analyses with an appropriate comparator population. OBJECTIVES: To examine, over a 3-year period, whether ivacaftor therapy affects pulmonary function and nutritional measures in patients with CF with a G551D mutation compared with patients with CF who are homozygous for the F508del mutation. METHODS: A propensity score was used to match patients with CF greater than or equal to 6 years of age who have a G551D mutation and received ivacaftor in clinical trials for up to 144 weeks with data from patients in the U.S. Cystic Fibrosis Foundation Patient Registry who are homozygous for the F508del mutation. Matching was based on variables including age, sex, weight for age, height for age, body mass index for age, % predicted FEV1, and chronic therapies (dornase alfa, inhaled antibiotics, inhaled and oral corticosteroids). MEASUREMENTS AND MAIN RESULTS: By calculating the annual estimated rate of decline in lung function for G551D patients receiving ivacaftor and comparing it with the rate of decline in lung function for matched F508del control patients, we show that the rate of lung function decline in G551D ivacaftor-treated patients was slower by nearly half. Moreover, treatment with ivacaftor is shown to improve body mass index and weight-for-age z scores for G551D patients over the 3-year analysis period. CONCLUSIONS: These findings suggest that ivacaftor is a disease-modifying therapy for the treatment of cystic fibrosis.

Liver involvement in the Hispanic population of North America with cystic fibrosis.

OBJECTIVES: The aim of the present article was to determine the prevalence of liver involvement in Hispanic patients with cystic fibrosis (CF) and identify associations with age and severity of liver involvement. METHODS: We used 1994-2005 Epidemiologic Study of CF data to compare abnormal liver findings between Hispanic and non-Hispanic white patients with CF. RESULTS: Of 30,727 patients with CF, 5015 had liver involvement. Of 1957 Hispanic patients, 20.8% had liver involvement compared with 16.0% of 28,770 non-Hispanic white patients (odds ratio [OR] 1.38, 95% confidence interval [CI] 1.23-1.54). This higher prevalence of liver involvement persisted after adjusting for demographics and meconium ileus and was especially high in the first year of life (adjusted OR 3.14, 95% CI 2.27-4.35). Ten percent of infants with only elevated liver enzymes progressed to more severe liver disease. CONCLUSIONS: The Hispanic population with CF has more liver involvement (both elevated liver enzymes and clinical liver disease) than the non-Hispanic white population with CF, especially during the first year of life.

Probability of treatment following acute decline in lung function in children with cystic fibrosis is related to baseline pulmonary function.

OBJECTIVE: 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. STUDY DESIGN: 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. RESULTS: 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. CONCLUSIONS: 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.

Dornase alfa (Pulmozyme).

PURPOSE OF REVIEW: Dornase alfa (Pulmozyme) is one of the most commonly used medications to treat the lung disease of cystic fibrosis (CF). As other respiratory medications have entered the clinical market, understanding the proper use and indication for dornase alfa is increasingly important. In addition, dornase alfa is being used to treat other medical conditions. This review covers recent publications and expanding indications. RECENT FINDINGS: Understanding dornase alfa's mechanism of action and impact on the pathophysiology of CF leads to an improved understanding of optimal therapy, ways to improve adherence and use with other medications. Most importantly, routine use of dornase alfa is associated with improved lung function and survival in patients with CF. Outside of CF, potential uses include treating patients with empyema or on mechanical ventilation. SUMMARY: Dornase alfa has been available for clinical use for nearly 20 years and is one of the most commonly used medications in patients with CF. Routine use is associated with a reduced rate of pulmonary deterioration and improved survival. Recent clinical reports suggest that dornase alfa may have clinical value with other medical problems such as complicated pneumonia and mechanically ventilated patients with atelectasis.

Newborn screening for cystic fibrosis.

PURPOSE OF REVIEW: Newborn screening for cystic fibrosis (CF) is now universal in the US and many other countries. The rapid expansion of screening has resulted in numerous publications identifying new challenges for healthcare providers. This review provides an overview of these publications and includes ideas on managing these challenges. RECENT FINDINGS: Most CF newborn screening algorithms involve DNA mutation analysis. As screening has expanded, new challenges have been identified related to carrier detection and inconclusive diagnoses. Early descriptions of infants with CF-related metabolic syndrome (CRMS) indicate that the natural history of this condition cannot be predicted. Early identification has also provided an opportunity to better understand the pathophysiology of CF. However, few studies have been conducted in infants with CF to determine optimal therapy and recommendations are largely anecdotal. SUMMARY: Newborn screening provides an opportunity to identify and begin treatment early in individuals with CF. Whereas a single, optimal approach to screening does not exist, all programs can benefit from new findings regarding sweat testing, carrier detection, early pathophysiology, and clinical outcomes.

Socioeconomic status and the likelihood of antibiotic treatment for signs and symptoms of pulmonary exacerbation in children with cystic fibrosis.

OBJECTIVE: To determine whether socioeconomic status (SES) influences the likelihood of antibiotic treatment of pulmonary exacerbations in patients with cystic fibrosis (CF). STUDY DESIGN: We used data on 9895 patients ≤ 18 years old from the Epidemiologic Study of CF. After establishing an individual baseline of clinical signs and symptoms, we ascertained whether antibiotics were prescribed when new signs/symptoms suggested a pulmonary exacerbation, adjusting for sex, presence of Pseudomonas aeruginosa, the number of new signs/symptoms, and baseline disease severity. RESULTS: In a 12-month period, 20.0% of patients <6 years of age, 33.8% of patients 6 to 12 years of age, and 41.4% of patients 13 to 18 years of age were treated with any (oral, intravenous (IV), or inhaled) antibiotics; the percentage receiving IV antibiotics was 7.3%, 15.2%, and 20.9%, respectively. SES had little effect on treatment for pulmonary exacerbation with any antibiotics, but IV antibiotics were prescribed more frequently for patients with lower SES. CONCLUSIONS: SES-related disparities in CF health outcomes do not appear to be explained by differential treatment of pulmonary exacerbations.

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.

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Impact of Pseudomonas and Staphylococcus infection on inflammation and clinical status in young children with cystic fibrosis.

OBJECTIVE: To assess the effects of Pseudomonas aeruginosa and Staphylococcus aureus infection on lower airway inflammation and clinical status in young children with cystic fibrosis (CF). STUDY DESIGN: We studied 111 children age < 6 years who had 2 P aeruginosa-positive oropharyngeal cultures within 12 months. We examined bronchoalveolar lavage fluid (BALF) inflammatory markers (ie, cell count, differential, interleukin [IL]-8, IL-6, neutrophil elastase), CF-related bacterial pathogens, exotoxin A serology, and clinical indicators of disease severity. RESULTS: Young children with CF with both upper and lower airway P aeruginosa infection had higher neutrophil counts, higher IL-8 and free neutrophil elastase levels, increased likelihood of positive exotoxin A titers, and lower Shwachman scores compared with those with positive upper airway cultures only. S aureus was associated with increased lower airway inflammation, and the presence of both P aeruginosa and S aureus had an additive effect on concentrations of lower airway inflammatory markers. BALF markers of inflammation were increased with the number of different bacterial pathogens detected. CONCLUSIONS: Young children with CF who have upper and lower airway P aeruginosa infection have increased endobronchial inflammation and poorer clinical status compared with those with only upper airway P aeruginosa infection. The independent and additive effects of S aureus on inflammation support the significance of polymicrobial infection in early CF lung disease.

Association of socioeconomic status with the use of chronic therapies and healthcare utilization in children with cystic fibrosis.

OBJECTIVE: To determine whether previously reported socioeconomic status (SES)-related disparities in cystic fibrosis (CF) health outcomes vary by the indicator used (median household income by zip code [MIZ], maternal educational attainment [MEA], and state insurance coverage [MA]), and whether these disparities can be explained by differences in medical treatment. STUDY DESIGN: A cross-sectional analysis of data on patients age <18 years from the Epidemiologic Study of Cystic Fibrosis (ESCF). RESULTS: Disease severity showed a similar inverse correlation with all 3 SES measures. The number of stable clinic visits was unrelated to SES. Patients with MA had more sick outpatient visits and more courses of intravenous (IV) antibiotics for pulmonary exacerbations, and were more likely to be prescribed all chronic therapies. Low-MIZ patients had slightly fewer sick visits and more courses of IV antibiotics, and were more likely to receive oral nutrition supplements but less likely to receive macrolide prescriptions. Low-MEA patients were less likely to receive IV antibiotics at home, more likely to receive oral nutrition supplements, but less likely to receive macrolide prescriptions. CONCLUSIONS: CF health outcomes are correlated with the SES spectrum, but these disparities are not explained by differential use of health services or prescription of chronic therapy. Future investigations should focus on the possible impact of environmental exposures and differences in disease self-management.

Relationship between inhaled corticosteroid therapy and rate of lung function decline in children with cystic fibrosis.

OBJECTIVE: To assess the relationship between inhaled corticosteroids (ICS) use and lung function decline in children with cystic fibrosis (CF) using the Epidemiologic Study of Cystic Fibrosis, an observational study of patients with CF in North America. STUDY DESIGN: We analyzed data from 2978 patients 6 to 17 years old enrolled in ESCF between 1994 to 2004. We estimated the rate of decline in forced expiratory volume in 1 second (FEV(1)) before and after starting ICS therapy with a piecewise linear continuous single change point model, adjusting for potentially confounding covariates. RESULTS: Before initiation of ICS, mean FEV(1) decline was -1.52% predicted/year (95% CI: -1.96 to -1.08% predicted/year). After initiation of ICS therapy, mean FEV(1) decline was -0.44% predicted/year (95% CI: -0.85 to -0.03% predicted/year), which was a significant change (P = .002). ICS use was associated with decreased height for age Z scores and increased insulin/oral hypoglycemic use. CONCLUSIONS: In this retrospective analysis of prospectively collected data, ICS therapy in patients with CF was associated with a significant reduction in the rate of FEV(1) decline, decreased linear growth, and increased insulin/oral hypoglycemic use.

Decreased total serum coenzyme-Q10 concentrations: a longitudinal study in children with cystic fibrosis.

OBJECTIVE: To assess total serum levels of coenzyme Q(10) (Co-Q(10)), an important antioxidant, in children with cystic fibrosis (CF) and to investigate an association between Co-Q(10) level and clinical outcome. STUDY DESIGN: Co-Q(10) levels were measured annually in a prospective cohort study of 381 children with CF. A total of 1092 serum levels of total Co-Q(10) were obtained by high-performance liquid chromatography and ultraviolet light detection. Associations of Co-Q(10) with demographic variables and clinical outcomes were investigated. RESULTS: Of the 381 initial total serum Co-Q(10) measurements, 188 were in the deficient range. Low Co-Q(10) was significantly more prevalent in patients with pancreatic insufficiency (PI) (55%) compared with patients with pancreatic sufficiency (PS) (3%); 22% of the patients with PI exhibited persistently low Co-Q(10) levels. Low Co-Q(10) levels were significantly associated with Pseudomonas aeruginosa colonization in patients with PI and CF under age 24 months, but not with subsequent lung function or hospitalization rates. Low Co-Q(10) levels were related to other markers of nutritional status, including total lipids, beta-carotene, and alpha-tocopherol. CONCLUSIONS: Persistently low total serum Co-Q(10) levels are common in children with CF and PI. A prospective study is indicated to determine whether Co-Q(10) supplementation in CF is beneficial.

A pilot study on the safety and efficacy of a novel antioxidant rich formulation in patients with cystic fibrosis.

BACKGROUND: Pancreatic insufficiency and a diminished bile acid pool cause malabsorption of important essential nutrients and other dietary components in cystic fibrosis (CF). Of particular significance is the malabsorption of fat-soluble antioxidants such as carotenoids, tocopherols and coenzyme Q(10) (CoQ(10)). Despite supplementation, CF patients are often deficient in these compounds, resulting in increased oxidative stress, which may contribute to adverse health effects. This pilot study was designed to evaluate the safety of a novel micellar formulation (CF-1) of fat-soluble nutrients and antioxidants and to determine its efficacy in improving plasma levels of these compounds and reducing inflammatory markers in induced sputum. METHODS: Ten CF subjects, ages 8 to 45 years old, were given orally 10 ml of the CF-1 formulation daily for 56 days after a 21-day washout period in which subjects stopped supplemental vitamin use except for a standard multivitamin. Plasma obtained at -3, 0 (baseline), 1, 2, 4, and 8 weeks was assayed for beta-carotene, gamma-tocopherol, retinol, and CoQ(10) as well as for safety parameters (comprehensive metabolic panel and complete blood count). In addition, pulmonary function was measured and induced sputum was assayed for markers of inflammation and quantitative bacterial counts both prior and during dosing. RESULTS: No serious adverse effects, laboratory abnormalities or elevated nutrient levels (above normal) were identified as related to CF-1. Supplementation with CF-1 significantly increased beta-carotene levels at all dosing time points when compared to screening and baseline. In addition, gamma-tocopherol and CoQ(10) significantly increased from baseline in all subjects. Induced sputum myeloperoxidase significantly decreased and there was a trend toward decreases in PMN elastase and total cell counts with CF-1. There was a significant inverse correlation between the antioxidant levels and induced sputum changes in IL-8 and total neutrophils. Lung function and sputum bacterial counts were unchanged. CONCLUSION: The novel CF-1 formulation safely and effectively increased plasma levels of important fat-soluble nutrients and antioxidants. In addition, improvements in antioxidant plasma levels were associated with reductions in airway inflammation in CF patients.

Pulmonary exacerbations and acute declines in lung function in patients with cystic fibrosis.

BACKGROUND: Patients with cystic fibrosis (CF) who experience acute declines in percent predicted FEV1 (ppFEV1 decreased ≥10% relative to baseline) are often not treated with antibiotics for pulmonary exacerbations (PEx), whereas other patients are treated even when they have not experienced a decline in lung function. METHODS: We analyzed 2 patient cohorts using 3 years of Epidemiologic Study of CF data. Cohort 1 (12,837 patients) experienced a ≥10% acute decline in ppFEV1 (n = 22,898) and Cohort 2 (10,416 patients) had a clinician-diagnosed PEx (n = 20,731). RESULTS: 70.7% of ≥10% decline events were treated with antibiotics; with intravenous antibiotics used 67.1% of the time. 32.0% of clinician-diagnosed PEx declined <10%; with intravenous antibiotics used 36.9% of the time. CONCLUSIONS: A clinician's decision to diagnose a PEx and treat with antibiotics often is not defined by measured lung function: a ≥10% FEV1 decline is not considered an absolute indication of a PEx and the lack of a decline does not contraindicate a PEx. Clinicians appear to use the history of prior PEx plus other variables as factors for diagnosing PEx.

Lung function decline is delayed but not decreased in patients with cystic fibrosis and the R117H gene mutation.

BACKGROUND: Patients with cystic fibrosis (CF) experience variable lung disease phenotypes. The R117H mutation is often associated with preserved lung function. Our objective was to compare the rate of lung function decline in patients with the R117H mutation and patients homozygous for the F508del mutation. METHODS: Rate of decline in percentage-of-predicted FEV1 (ppFEV1) was analyzed using the 2006-2010 US CF Foundation Patient Registry. RESULTS: 4-year rate of decline was slower in 156 R117H patients compared with 6251 F508del patients (-0.61 vs -2.03 ppFEV1/year, P<0.001). Rates of decline in children were slower in R117H vs F508del patients (6-12-year-olds: +0.73 vs -1.91 ppFEV1/year, P<0.001 and 13-17-year-olds: -1.55 vs -2.66 ppFEV1/year, P=0.046), whereas rates in adults were not significantly different (18-24-year-olds: -1.52 vs -2.12, P=0.26 and ≥25-year-olds: -1.17 vs -1.40, P=0.33). CONCLUSIONS: These findings are consistent with a delayed onset, but ultimately similar progression, of lung disease in R117H compared with homozygous F508del patients.

Recovery of lung function following a pulmonary exacerbation in patients with cystic fibrosis and the G551D-CFTR mutation treated with ivacaftor.

BACKGROUND: Pulmonary exacerbations (PEx) are associated with acute loss of lung function that is often not recovered after treatment. We investigated lung function recovery following PEx for ivacaftor- and placebo-treated subjects. METHODS: Short- and long-term pulmonary function recovery data after PEx were summarized from a placebo-controlled trial in 161 cystic fibrosis patients≥12years old with the G551D-CFTR mutation (NCT00909532). Short-term recovery was measured 2 to 8weeks after treatment, and long-term recovery was determined at the end-of-study, both compared with baseline measured just prior to the PEx. RESULTS: Fewer patients receiving ivacaftor experienced a PEx than patients receiving placebo (33.7% vs. 56.4%; P=0.004) and had a lower adjusted incidence rate of PEx (0.589 vs. 1.382; P<0.001). The proportion of PEx followed by full short-term recovery of percent predicted forced expiratory volume in 1s was similar (ivacaftor vs. placebo, 57.1% vs. 53.7), as was the proportion of patients having long-term recovery (46.4% vs. 47.7%). CONCLUSIONS: Ivacaftor treatment reduces the frequency of PEx but does not improve on the rate of complete lung function recovery after PEx when compared with placebo.

Risk factors for rate of decline in forced expiratory volume in one second in children and adolescents with cystic fibrosis.

OBJECTIVES: To characterize the rate of decline of forced expiratory volume in 1 second (FEV(1)) in children and adolescents with cystic fibrosis and to identify and compare risk factors associated with FEV(1) decline. STUDY DESIGN: The rate of decline in FEV(1)% predicted over 3 to 6 years in 3 different age groups was determined. Risk factors for decline were identified and compared among and within age groups as a function of disease severity with repeated-measures, mixed-model regression. RESULTS: Mean (+/-SD) baseline FEV(1)% predicted was 88.4% +/- 20.5% for 6- to 8-year-olds (n = 1811), 85.3% +/- 20.8% for 9- to 12-year-olds (n = 1696), and 78.4% +/- 22.0% for 13- to 17-year-olds (n = 1359). Decline in FEV(1)% predicted/year was -1.12, -2.39, and -2.34, respectively. High baseline FEV(1) and persistent crackles were significant independent risk factors for decline across all age groups. Female sex, Pseudomonas aeruginosa infection, low weight-for-age, sputum, wheezing, sinusitis, pulmonary exacerbations treated with intravenous antibiotics, elevated liver test results, and pancreatic insufficiency were also identified as independent risk factors in some age groups. CONCLUSIONS: This study identifies risk factors for FEV(1) decline in children and adolescents with cystic fibrosis. Clinicians should not be reassured by high lung function, particularly in young children, because this factor, among others, is independently associated with steeper decline in FEV(1).