FEV1 Variability Predicts Lung Transplant or Mortality in Cystic Fibrosis Patients in the US.

RATIONALE: Declines in percent predicted Forced Expiratory Volume in 1 Second (ppFEV1) are an important marker of clinical progression of Cystic Fibrosis (CF). OBJECTIVES: We examined ppFEV1 variability on a combined outcome of lung transplant or death. METHODS: We estimated the association between ppFEV1 variability and the combined outcome of lung transplant or death. We included children ages 8 years and above with CF and two prior years of ppFEV1 data before baseline between 2005 and 2021. We defined ppFEV1 increased variability as any relative increase or decrease of at least 10% in ppFEV1 from a two-year averaged baseline. A marginal structural Cox proportional hazards model was used. We examined a cumulative measure of ppFEV1 variability, defined as the cumulative proportion of visits with ppFEV1 variability at each visit. Kaplan-Meier survival curves were generated based upon quartiles of the cumulative distribution of ppFEV1 variability. MEASUREMENTS AND MAIN RESULTS: We included 9,706 CF patients in our cohort. Median age at cohort entry was 8.3 (IQR 8.2 - 8.4) years, 50% of patients were female, 94% white, and median baseline ppFEV1 was 94.4 (IQR 81.6 - 106.1). The unadjusted HR for increased ppFEV1 variability on lung transplant/mortality was 4.13 (95% CI 3.48 - 4.90) and the weighted HR was 1.49 (95% CI 1.19 - 1.86). Survival curves stratified by quartile of cumulative variability demonstrated an increased hazard of lung transplant/mortality as the proportion of cumulative ppFEV1 variability increased. CONCLUSIONS: We found a strong association between ppFEV1 variability and lung transplant or mortality in a cohort of people with CF in the US.

The impact of switching to race-neutral reference equations on FEV1 percent predicted among people with cystic fibrosis.

RATIONALE: The American Thoracic Society recommended switching to race-neutral spirometry reference equations, as race is a social construct and to avoid normalizing disparities in lung function due to structural racism. Understanding the impact of the race-neutral equations on percent predicted forced expiratory volume in one second (ppFEV1) in people with cystic fibrosis (PwCF) will help prepare patients and providers to interpret pulmonary function test results. OBJECTIVE(S): To quantify the impact of switching from Global Lung Initiative (GLI) 2012 race-specific to GLI 2022 Global race-neutral reference equations on the distribution of ppFEV1 among PwCF of different races. METHODS: Cross-sectional analysis of FEV1 among PwCF ages ≥6 years in the 2021 U.S. Cystic Fibrosis Foundation Patient Registry. We describe the absolute difference in ppFEV1 between the two reference equations by reported race and the effect of age and height on this difference. RESULTS: With the switch to GLI Global, ppFEV1 will increase for White (median increase 4.7, (IQR: 3.1; 6.4)) and Asian (2.6 (IQR: 1.6; 3.7)) individuals and decrease for Black individuals (-7.7, (IQR: -10.9; -5.2)). Other race categories will see minimal changes in median ppFEV1. Individuals with higher baseline ppFEV1 and younger age will see a greater change in ppFEV1 (i.e., a greater improvement among White and Asian individuals and a greater decline among Black individuals). CONCLUSIONS: Switching from GLI 2012 race-specific reference equations to GLI 2022 Global race-neutral equations will result in larger reductions in ppFEV1 among Black individuals with CF than increases among White and Asian people with CF.

Circulating biomarkers of airflow limitation across the life span.

BACKGROUND: Airflow limitation is a hallmark of chronic obstructive pulmonary disease, which can develop through different lung function trajectories across the life span. There is a need for longitudinal studies aimed at identifying circulating biomarkers of airflow limitation across different stages of life. OBJECTIVES: This study sought to identify a signature of serum proteins associated with airflow limitation and evaluate their relation to lung function longitudinally in adults and children. METHODS: This study used data from 3 adult cohorts (TESAOD [Tucson Epidemiological Study of Airway Obstructive Disease], SAPALDIA [Swiss Cohort Study on Air Pollution and Lung and Heart Diseases in Adults], LSC [Lovelace Smoker Cohort]) and 1 birth cohort (TCRS [Tucson Children's Respiratory Study]) (N = 1940). In TESAOD, among 46 circulating proteins, we identified those associated with FEV1/forced vital capacity (FVC) percent (%) predicted levels and generated a score based on the sum of their z-scores. Cross-sectional analyses were used to test the score for association with concomitant lung function. Longitudinal analyses were used to test the score for association with subsequent lung function growth in childhood and decline in adult life. RESULTS: After false discovery rate adjustment, serum levels of 5 proteins (HP, carcinoembryonic antigen, ICAM1, CRP, TIMP1) were associated with percent predicted levels of FEV1/FVC and FEV1 in TESAOD. In cross-sectional multivariate analyses the 5-biomarker score was associated with FEV1 % predicted in all adult cohorts (meta-analyzed FEV1 decrease for 1-SD score increase: -2.9%; 95% CI: -3.9%, -1.9%; P = 2.4 × 10-16). In multivariate longitudinal analyses, the biomarker score at 6 years of age was inversely associated with FEV1 and FEV1/FVC levels attained by young adult life (P = .02 and .005, respectively). In adults, persistently high levels of the biomarker score were associated with subsequent accelerated decline of FEV1 and FEV1/FVC (P = .01 and .001). CONCLUSIONS: A signature of 5 circulating biomarkers of airflow limitation was associated with both impaired lung function growth in childhood and accelerated lung function decline in adult life, indicating that these proteins may be involved in multiple lung function trajectories leading to chronic obstructive pulmonary disease.

A Pilot Randomized Clinical Trial of Pediatric Cystic Fibrosis Pulmonary Exacerbations Treatment Strategies.

Rationale: Despite the high prevalence and clear morbidity of cystic fibrosis (CF) pulmonary exacerbations (PEx), there have been no published clinical trials of outpatient exacerbation management. Objectives: To assess the feasibility of a pediatric clinical trial in which treatment of mild PEx is assigned randomly to immediate oral antibiotics or tailored therapy (increased airway clearance alone with oral antibiotics added only for prespecified criteria). The outcome on which sample size was based was the proportion of tailored therapy participants who avoided oral antibiotics during the 28 days after randomization. Methods: In this randomized, open-label, pilot feasibility study at 10 U.S. sites, children 6-18 years of age with CF were enrolled at their well baseline visits and followed through their first randomized PEx. Results: One hundred twenty-one participants were enrolled, of whom 94 (78%) reported symptoms of PEx at least once; of these, 81 (86%) had at least one exacerbation that met randomization criteria, of whom 63 (78%) were randomized. Feasibility goals were met, including enrollment, early detection of symptoms of PEx, and ability to randomize. Among the 33 participants assigned to tailored therapy, 10 (30%) received oral antibiotics, while 29 of 30 (97%) assigned to immediate antibiotics received oral antibiotics. The avoidance of oral antibiotics in 70% (95% confidence interval, 54-85%) was statistically significantly different from our null hypothesis that <10% of participants assigned to the tailored therapy arm would avoid antibiotics. Conclusions: Our pilot study demonstrates that conducting a randomized trial of oral antibiotic treatment strategies for mild PEx in children with CF is feasible and that assignment to a tailored therapy arm may reduce antibiotic exposure. Clinical trial registered with www.clinicaltrials.gov (NCT04608019).

Lung Function Decline in Cystic Fibrosis: Impact of Data Availability and Modeling Strategies on Clinical Interpretations.

Rationale: Studies estimating the rate of lung function decline in cystic fibrosis have been inconsistent regarding the methods used. How the methodology used impacts the validity of the results and comparability between studies is unknown. Objectives: The Cystic Fibrosis Foundation established a work group whose tasks were to examine the impact of differing approaches to estimating the rate of decline in lung function and to provide analysis guidelines. Methods: We used a natural history cohort of 35,252 individuals with cystic fibrosis aged ⩾6 years in the Cystic Fibrosis Foundation Patient Registry (CFFPR), 2003-2016. Modeling strategies using linear and nonlinear forms of marginal and mixed-effects models, which have previously quantified the rate of forced expiratory volume in 1 second (FEV1) decline (percent predicted per year), were evaluated under clinically relevant scenarios of available lung function data. Scenarios varied by sample size (overall CFFPR, medium-sized cohort of 3,000 subjects, and small-sized cohort of 150), data collection/reporting frequency (encounter, quarterly, and annual), inclusion of FEV1 during pulmonary exacerbation, and follow-up length (<2 yr, 2-5 yr, entire duration). Results: Rate of FEV1 decline estimates (percent predicted per year) differed between linear marginal and mixed-effects models; overall cohort estimates (95% confidence interval) were 1.26 (1.24-1.29) and 1.40 (1.38-1.42), respectively. Marginal models consistently estimated less rapid lung function decline than mixed-effects models across scenarios, except for short-term follow-up (both were ∼1.4). Rate of decline estimates from nonlinear models diverged by age 30. Among mixed-effects models, nonlinear and stochastic terms fit best, except for short-term follow-up (<2 yr). Overall CFFPR analysis from a joint longitudinal-survival model implied that an increase in rate of decline of 1% predicted per year in FEV1 was associated with a 1.52-fold (52%) increase in the hazard of death/lung transplant, but the results exhibited immortal cohort bias. Conclusions: Differences were as high as 0.5% predicted per year between rate of decline estimates, but we found estimates were robust to lung function data availability scenarios, except short-term follow-up and older age ranges. Inconsistencies among previous study results may be attributable to inherent differences in study design, inclusion criteria, or covariate adjustment. Results-based decision points reported herein will support researchers in selecting a strategy to model lung function decline most reflective of nuanced, study-specific goals.

Rate of Lung Function Decline in People with Cystic Fibrosis Having a Residual Function Gene Mutation.

INTRODUCTION: Cystic fibrosis (CF) is an autosomal recessive disease caused by mutations in the CF transmembrane conductance regulator (CFTR) gene. Approximately 5% of people with CF have residual function (RF) CFTR mutations that result in partially retained CFTR activity. Published literature on disease trajectory among those with RF mutations is limited. In this retrospective study, we characterized lung function decline across different age groups in CFTR modulator-untreated people with CF heterozygous for F508del and an RF mutation (F/RF). METHODS: Rate of decline in percent predicted forced expiratory volume in 1 s (ppFEV1) was analyzed using data from the US CF Foundation Patient Registry (2006-2014) in F/RF (all), F/RF (excluding R117H), and F508del homozygous (F/F) cohorts. Annual rates of ppFEV1 decline were estimated over 2-year periods based on calendar year. Subgroup analyses by age [6-12 (children), 13-17 (adolescents), 18-24 (young adults), and ≥ 25 years (adults)] were performed. RESULTS: The estimated annualized rate of ppFEV1 decline was - 0.70 percentage points per year (95% CI -1.09, -0.30) in the F/RF (all) cohort (N = 1242) versus -1.91 percentage points per year (95% CI -2.01, -1.80) in the F/F cohort (N = 11,916) [difference, 1.29 percentage points per year (95% CI 0.88, 1.70); P < 0.001]. In the F/RF (all) cohort, all age groups demonstrated lung function decline ranging from -0.30 to -1.38. In the F/RF (excluding R117H) cohort, the rate of decline was -1.05 percentage points per year (95% CI -1.51, -0.60) [difference versus F/F cohort, 0.95 percentage points per year (95% CI 0.48, 1.41; P < 0.001); not statistically significant in children and young adults]. CONCLUSION: Progressive lung function decline was observed in people with F/RF genotypes across all assessed age groups, reinforcing the importance of early intervention and clinical monitoring to preserve lung function in all people with CF.

In people with cystic fibrosis, lung function typically decreases over time and is linked to the severity of the disease. How fast lung function decreases (referred to as the rate of lung function decline) in cystic fibrosis depends on the specific mutations (changes) in the CFTR gene (which causes the disease). Lung function decline has been well studied in some mutation groups, but not many previous studies have looked at lung function decline in people with one copy of the F508del-CFTR mutation (which is the most common CFTR mutation and results in little to no functional CFTR protein) and another CFTR mutation called a residual function mutation (referred to as people with F/RF genotypes). We used data from the US Cystic Fibrosis Foundation Patient Registry (which collects information on the health of people in the USA who have cystic fibrosis), to look at the rate of lung function decline in people with F/RF genotypes. We found that people with cystic fibrosis who have F/RF genotypes experience lung function loss over time. We also found that this lung function loss occurred in people of all ages with F/RF genotypes. This finding supports the importance of early treatment to help prevent lung function loss in all people with cystic fibrosis, including people with F/RF genotypes.

Club cell secretory protein and lung function in children with cystic fibrosis.

BACKGROUND: Club cell secretory protein (CC16) exerts anti-inflammatory functions in lung disease. We sought to determine the relation of serum CC16 deficits and genetic variants that control serum CC16 to lung function among children with cystic fibrosis (CF). METHODS: We used longitudinal data from CF children (EPIC Study) with no positive cultures for Pseudomonas aeruginosa prior to enrollment. Circulating levels of CC16 and an inflammatory score (generated from CRP, SAA, calprotectin, G-CSF) were compared between participants with the lowest and highest FEV1 levels in adolescence (LLF and HLF groups, respectively; N = 130-per-group). Single nucleotide variants (SNVs) in the SCGB1A1, EHF-APIP loci were tested for association with circulating CC16 and with decline of FEV1 and FEV1/FVC% predicted levels between ages 7-16 using mixed models. RESULTS: Compared with the HLF group, the LLF group had lower levels of CC16 (geometric means: 8.2 vs 6.5 ng/ml, respectively; p = 0.0002) and higher levels of the normalized inflammatory score (-0.21 vs 0.21, p = 0.0007). Participants in the lowest CC16 and highest inflammation tertile had the highest odds for having LLF (p<0.0001 for comparison with participants in the highest CC16 and lowest inflammation tertile). Among seven SNVs associated with circulating CC16, the top SNV rs3741240 was associated with decline of FEV1/FVC and, marginally, FEV1 (p = 0.003 and 0.025, respectively; N = 611 participants, 20,801 lung function observations). CONCLUSIONS: Serum CC16 deficits are strongly associated with severity of CF lung disease and their effects are additive with systemic inflammation. The rs3741240 A allele is associated with low circulating CC16 and, possibly, accelerated lung function decline in CF.

Association of Intensity of Antipseudomonal Antibiotic Therapy With Risk of Treatment-Emergent Organisms in Children With Cystic Fibrosis and Newly Acquired Pseudomonas Aeruginosa.

BACKGROUND: While Pseudomonas aeruginosa (Pa) eradication regimens have contributed to a decline in Pa prevalence in people with cystic fibrosis (CF), this antibiotic exposure might increase the risk of acquisition of drug-resistant organisms. This study evaluated the association between antipseudomonal antibiotic exposure intensity and acquisition risk of drug-resistant organisms among children with CF and new Pa infection. METHODS: We utilized data from the Early Pseudomonas Infection Control Clinical Trial (EPIC CT), a randomized controlled trial comparing Pa eradication strategies in children with CF and new Pa. The exposure was the number of weeks of oral or inhaled antipseudomonal antibiotics or ever versus never treatment with intravenous antipseudomonal antibiotics during the 18 months of EPIC CT participation. Primary outcomes were risks of acquisition of several respiratory organisms during 5 years of follow-up after EPIC CT estimated using Cox proportional hazards models separately for each specific organism. RESULTS: Among 249 participants, there was no increased acquisition risk of any organism associated with greater inhaled antibiotic exposure. With each additional week of oral antibiotics, there was an increased hazard of Achromobacter xylosoxidans acquisition (HR, 1.24; 95% CI: 1.02-1.50; P = .03). Treatment with intravenous antibiotics was associated with an increased hazard of acquisition of multidrug-resistant Pa (HR, 2.47; 95% CI: 1.28-4.78; P = .01) and MRSA (HR, 1.57; 95% CI: 1.03-2.40; P = .04). CONCLUSIONS: Results from this study illustrate the importance of making careful antibiotic choices to balance the benefits of antibiotics in people with CF while minimizing risk of acquisition of drug-resistant organisms.

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.

Oral antibiotic prescribing patterns for treatment of pulmonary exacerbations in two large pediatric CF centers.

INTRODUCTION: Oral antibiotics are frequently prescribed for outpatient pulmonary exacerbations (PEx) in children with cystic fibrosis (CF). This study aimed to characterize oral antibiotic use for PEx and treatment outcomes at two large US CF centers. METHODS: Retrospective, descriptive study of oral antibiotic prescribing practices among children with CF ages 6-17 years over 1 year. The care setting for antibiotic initiation (clinic or phone encounter) was determined and outcomes were compared. RESULTS: A total of 763 oral antibiotic courses were prescribed to 312 patients aged 6-17 years (77% of 403 eligible patients) with a median of two courses per year (range: 1-10). Fifty-eight percent of prescriptions were provided over the phone. Penicillin was the most commonly prescribed antibiotic class (36% of prescriptions) but differences in antibiotic class prescriptions were noted between the two centers. Hospitalizations occurred within 3 months following 19% of oral antibiotic courses. Forced expiratory volume in 1 s (FEV1 ) recovered to within 90% of prior baseline within 6 months in 87% of encounters; the mean (SD) % recovery was 99.6% (12.1%) of baseline. Outcomes did not differ between phone and clinic prescriptions. CONCLUSIONS: Phone prescriptions, commonly excluded in studies of PEx, made up more than half of all oral antibiotic courses. Heterogeneity in prescribing patterns was observed between the two centers. Most patients had improvement in FEV1 returning to near their prior baseline, but hospitalizations occurred in one-fifth following oral antibiotic treatment. Efforts to optimize PEx treatment must consider care that occurs over the phone; this is particularly important as the use of telemedicine increases.

Predictors of pulmonary exacerbation treatment in cystic fibrosis.

BACKGROUND: Most studies of pulmonary exacerbations (PEx) in cystic fibrosis (CF) focus on intravenous (IV)-treated PEx, though most PEx are treated with oral antibiotics. Our objectives were to describe predictors of antibiotic choice and outcomes for PEx initially identified in clinic. METHODS: For each patient in the U.S. CF Foundation Patient Registry, we selected the first PEx recorded at a clinic visit in 2013-14 following a clinic visit without a PEx. We used multivariable logistic regression to determine associations between clinical characteristics and antibiotic treatment choice. We determined outcomes in the 90 days after the first PEx. RESULTS: Among 14,265 patients with a PEx initially identified in clinic, 21.4% received no antibiotics, 61.5% received new oral and/or inhaled antibiotics, and 17.0% had IV antibiotics within 14 days. Compared to IV antibiotics, patients more likely to receive new oral and/or inhaled antibiotics: were male, <13 years old, had BMI >10th percentile or 18.5 kg/m2, >90 days between clinic visits, FEV1 > 70% predicted at the PEx, no prior-year IV-treated PEx, FEV1 decline <10% predicted, and private insurance. Following the PEx, 30.3% of patients had no clinical encounters within 90 days. Treatment with IV antibiotics within 90 days occurred for 23.7% treated without antibiotics, 22.8% of new oral and/or inhaled antibiotics, and 27.1% of IV antibiotics. CONCLUSION: Most PEx identified in clinic are treated with new oral and/or inhaled antibiotics. Markers of disease severity are associated with antibiotic treatment choice. Many patients had no follow-up evaluation within 90 days of treatment.

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.

Cystic Fibrosis Transmembrane Conductance Regulator Genotype, Not Circulating Catecholamines, Influences Cardiovascular Function in Patients with Cystic Fibrosis.

BACKGROUND: Cystic fibrosis (CF) is a genetic disease affecting multiple organ systems of the body and is characterized by mutation in the gene coding for the cystic fibrosis transmembrane conductance regulator (CFTR). Previous work has shown that a single dose of aß-agonist increases cardiac output (Q) and stroke volume (SV) and decreases systemic vascular resistance (SVR) in healthy subjects. This effect is attenuated in patients with CF; however, the mechanism is unknown. Potential explanations for this decreased cardiovascular response to a ß-agonist in CF include inherent cardiovascular deficits secondary to the CFTR mutation, receptor desensitization from prolonged ß-agonist use as part of clinical care, or inhibited drug delivery to the bloodstream due to mucus buildup in the lungs. This study sought to determine the effects of endogenous epinephrine (EPI) and norepinephrine (NE) on cardiovascular function in CF and to evaluate the relationship between cardiovascular function and CFTR F508del mutation. METHODS: A total of 19 patients with CF and 31 healthy control subjects completed an assessment of Q (C2H2 rebreathing), SV (calculated from Q and heart rate [HR]), Q and SV indexed to body surface area (BSA, QI, and SVI, respectively), SVR (through assessment of Q and mean arterial blood pressure [MAP]), and HR (from 12-lead electrocardiogram [ECG]) at rest along with plasma measures of EPI and NE. We compared subjects by variables of cardiovascular function relative to EPI and NE, and also based on genetic variants of the F508del mutation (homozygous deletion for F508del, heterozygous deletion for F508del, or no deletion of F508del). RESULTS: Cystic fibrosis patients demonstrated significantly lower BSA (CF = 1.71 ± 0.05 m2 vs healthy = 1.84 ± 0.04 m2, P = .03) and SVI (CF = 30.6 ± 2.5 mL/beat/m2 vs healthy = 39.9 ± 2.5 mL/beat/m2, P = .02) when compared with healthy subjects. Cystic fibrosis patients also demonstrated lower Q (CF = 4.58 ± 0.36 L/min vs healthy = 5.71 ± 0.32 L/min, P = .03) and SV (CF = 54 ± 5.5 mL/beat vs healthy = 73.3 ± 4.5 mL/beat, P = .01), and a higher HR (CF = 93.2 ± 3.9 bpm vs healthy = 80.5 ± 2.7 bpm, P < .01) and SVR (CF = 2082 ± 156 dynes*s/cm-5 vs healthy = 1616 ± 74 dynes*s/cm-5, P = .01) compared with healthy subjects. Furthermore, CF patients demonstrated a lower SV (P < .01) corrected for NE when compared with healthy subjects. No significant differences were seen in HR or Q relative to NE, or SVR relative to EPI. Differences were seen in SV (F(2,14) = 7.982, P < .01) and SV index (F(2,14) = 2.913, P = .08) when patients with CF were stratified according to F508del mutation (number of deletions). CONCLUSIONS: Individuals with CF have lower cardiac and peripheral hemodynamic function parameters at rest. Furthermore, these results suggest that impairment in cardiovascular function is likely the result of F508del CFTR genotype, rather than receptor desensitization or inhibited drug delivery.

Sleep-Disordered Breathing is Associated With Increased Mortality in Hospitalized Infants With Congenital Heart Disease.

STUDY OBJECTIVES: Sleep-disordered breathing (SDB) has adverse cardiovascular effects in children and adults. In adults with cardiac disease, SDB is highly prevalent and confers increased mortality risk. It is unknown if SDB confers a similar risk in infants with congenital heart disease (CHD). We evaluated clinical and economic outcomes associated with SDB among inpatient infants with CHD in the United States from 1997-2012. METHODS: This retrospective, cross-sectional study used discharge data from the Kids' Inpatient Database. Inclusion criteria included diagnosed CHD and age younger than 1 year. Exclusion criteria included apnea of prematurity, cardiac surgery during admission, and invasive mechanical ventilation. Generalized linear models were used to assess outcomes of mortality, length of stay, and total charges after controlling for SDB, clinical characteristics, hospital characteristics, and economic factors. RESULTS: Across 461,778 inpatient infant cases of CHD from 1997-2012, 4,839 involved SDB (14% obstructive, 4% central, 82% not specified). Multivariable analyses show that central sleep apnea was independently associated with increased risk of inpatient mortality (odds ratio 4.3), 92% longer inpatient stay, and 112% higher total charges when compared to infants with CHD without comorbid SDB (P < .05). Obstructive and unspecified SDB were associated with longer adjusted lengths of stay (56% and 18%, respectively) and higher charges (48% and 21%, respectively) relative to infants with CHD without comorbid SDB (P < .001). CONCLUSIONS: SDB, particularly central sleep apnea, was independently associated with worse outcomes in hospitalized infants with CHD. Further research on whether treatment of SDB in infants with CHD can abrogate adverse patient outcomes is needed.

Exercise Stroke Volume in Adult Cystic Fibrosis: A Comparison of Acetylene Pulmonary Uptake and Oxygen Pulse.

Cardiac hemodynamic assessment during cardiopulmonary exercise testing (CPET) is proposed to play an important role in the clinical evaluation of individuals with cystic fibrosis (CF). Cardiac catheterization is not practical for routine clinical CPET. Use of oxygen pulse (O2pulse) as a noninvasive estimate of stroke volume (SV) has not been validated in CF. This study tested the hypothesis that peak exercise O2pulse is a valid estimate of SV in CF. Measurements of SV via the acetylene rebreathe technique were acquired at baseline and peak exercise in 17 mild-to-moderate severity adult CF and 25 age-matched healthy adults. We calculated O2pulse=V.O2HR . Baseline relationships between SV and O2pulse were significant in CF (r = .80) and controls (r = .40), persisting to peak exercise in CF (r = .63) and controls (r = .73). The standard error of estimate for O2pulse-predicted SV with respect to measured SV was similar at baseline (14.1 vs 20.1 mL) and peak exercise (18.2 vs 13.9 mL) for CF and controls, respectively. These data suggest that peak exercise O2pulse is a valid estimate of SV in CF. The ability to noninvasively estimate SV via O2pulse during routine clinical CPET can be used to improve test interpretation and advance our understanding of the impact cardiac dysfunction has on exercise intolerance in CF.

Protective effect of breastfeeding on recurrent cough in adulthood.

RATIONALE: Breastfeeding protects from respiratory infections in early life but its relationship to recurrent cough and other respiratory outcomes in adult life is not well established. METHODS: Infant feeding practices were assessed prospectively in the Tucson Children's Respiratory Study, a non-selected birth cohort and categorised into formula from birth or introduced <1 month, formula introduced ≥1 to <4 months and exclusive breastfeeding for ≥4 months. Infant feeding was assessed as an ordinal variable representing an increasing dose of breastmilk across the three categories. Recurrent cough was defined at 22, 26 and 32 years as ≥2 episodes of cough without a cold lasting 1 week during the past year. Covariates included participant sex, race/ethnicity and smoking as well as parental smoking, education, age and asthma. Covariates were evaluated as potential confounders for the relation between infant feeding and adult outcomes. RESULTS: Of the 786 participants, 19% breastfed <1 month, 50% breastfed ≥1 to <4 months and 31% breastfed ≥4 months. The prevalence of recurrent cough at 22, 26 and 32 years was 17%, 15% and 16%, respectively. Each ordinal increase in breastfeeding duration was associated with a decreased risk of recurrent cough in adult life: adjusted OR=0.71, (95% CI: 0.56 to 0.89), p=0.004. Additional adjustment for concurrent adult asthma, wheeze, smoking and lung volume did not change these results. CONCLUSION: Longer duration of breastfeeding reduces the risk of recurrent cough in adult life, regardless of smoking and other respiratory symptoms, suggesting long-term protective effects on respiratory health.

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.