Metabolomics analysis of bronchoalveolar lavage fluid predicts unique features of the lower airway in pediatric cystic fibrosis.

BACKGROUND: Progressive, obstructive lung disease resulting from chronic infection and inflammation is the leading cause of morbidity and mortality in persons with cystic fibrosis (PWCF). Metabolomics and next -generation sequencing (NGS) of airway secretions can allow for better understanding of cystic fibrosis (CF) pathophysiology. In this study, global metabolomic profiling on bronchoalveolar lavage fluid (BALF) obtained from pediatric PWCF and disease controls (DCs) was performed and compared to lower airway microbiota, inflammation, and lung function. METHODS: BALF was collected from children undergoing flexible bronchoscopies for clinical indications. Metabolomic profiling was performed using a platform developed by Metabolon Inc. Total bacterial load (TBL) was measured using quantitative polymerase chain reaction (qPCR), and bacterial communities were characterized using 16S ribosomal RNA (rRNA) sequencing. Random Forest Analysis (RFA), principal component analysis (PCA), and hierarchical clustering analysis (HCA) were performed. RESULTS: One hundred ninety-five BALF samples were analyzed, 142 (73 %) from PWCF. Most metabolites (425/665) and summed categories (7/9) were significantly increased in PWCF. PCA of the metabolomic data revealed CF BALF exhibited more dispersed clustering compared to DC BALF. Higher metabolite concentrations correlated with increased inflammation, increased abundance of Staphylococcus, and decreased lung function. CONCLUSIONS: The lower airway metabolome of PWCF was defined by a complex expansion of metabolomic activity. These findings could be attributed to heightened inflammation in PWCF and aspects of the CF airway polymicrobial ecology. CF-specific metabolomic features are associated with the unique underlying biology of the CF airway.

Virtual interviews and equity: The pediatric pulmonary fellow perspective.

BACKGROUND AND OBJECTIVES: The SARS-CoV-2 pandemic shifted medical training programs to utilize virtual interviews (VIs) starting with the 2020 interview cycle. Fellowship interviews continue in the virtual format. It is unknown how this shift has affected equity for applicants as compared to in-person interviews. Equity in this study includes consideration of the opportunity for an applicant to accept, access, and conduct a VI. This study assessed pediatric pulmonary fellows' perception of equity associated with VIs and preferences for future cycles. METHODS: An anonymous survey link was emailed to Pediatric Pulmonology Program Directors to disseminate to incoming and first-year pediatric pulmonary fellows who participated in the 2022-2023 and 2021-2022 VI seasons. Responses were summarized by frequency and percentages. Inductive coding was used to thematically analyze free-text responses. RESULTS: Nearly 30% of eligible incoming and first-year pulmonary fellows (n = 35/119, 29.4%) completed the survey. Seventy-four percent felt that VIs reduce inequities as compared to in-person interviews. Sixty percent felt that VIs were the most equitable format, and 51% chose a VI as their preferred future format. Important practice considerations to promote equity for future VIs included providing applicants with instruction for the expected dress code, followed by providing applicants with virtual technology (91% and 89% of respondents ranked as at least "somewhat important," respectively). CONCLUSION: VIs were perceived as a more equitable interview format by pediatric pulmonology fellows compared to in-person interviews in our study. To increase equity for VIs, program directors can consider additional adaptations such as providing standardized instruction for dress code and providing the required technology.

Codesign of remote data collection for chronic management of pediatric home mechanical ventilation.

INTRODUCTION: Outpatient monitoring of children using invasive home mechanical ventilation (IHMV) is recommended, but access to care can be difficult. This study tested if remote (home-based) data collection was feasible and acceptable in chronic IHMV management. METHODS: A codesign study was conducted with an IHMV program, home nurses, and English- and Spanish-speaking parent-guardians of children using IHMV (0-17 years; n = 19). After prototyping, parents used a remote patient monitoring (RPM) bundle to collect patient heart rate, respiratory rate (RR), oxygen saturation, end-tidal carbon dioxide (EtCO2 ), and ventilator pressure/volume over 8 weeks. User feedback was analyzed using qualitative methods and the System Usability Scale (SUS). Expected marginal mean differences within patient measures when awake, asleep, or after a break were calculated using mixed effects models. RESULTS: Patients were a median 2.9 years old and 11 (58%) took breaks off the ventilator. RPM data were entered on a mean of 83.7% (SD ± 29.1%) weeks. SUS scores were 84.8 (SD ± 10.5) for nurses and 91.8 (SD ± 10.1) for parents. Over 90% of parents agreed/strongly agreed that RPM data collection was feasible and relevant to their child's care. Within-patient comparisons revealed that EtCO2 (break-vs-asleep 2.55 mmHg, d = 0.79 [0.42-1.15], p < .001; awake-vs-break 1.48, d = -0.49 [0.13-0.84], p = .02) and RR (break-vs-asleep 16.14, d = 2.12 [1.71-2.53], p < .001; awake-vs-break 3.44, d = 0.45 [0.10-0.04], p = .03) were significantly higher during ventilator breaks. CONCLUSIONS: RPM data collection in children with IHMV was feasible, acceptable, and captured clinically meaningful vital sign changes during ventilator breaks, supporting the clinical utility of RPM in IHMV management.

Diversity, Equity, and Inclusion in the Pediatric Pulmonary Workforce: An Official American Thoracic Society Workshop Report.

Despite growing recognition of the need for increased diversity among students, trainees, and faculty in health care, the medical workforce still lacks adequate representation from groups historically underrepresented in medicine (URiM). The subspecialty field of pediatric pulmonology is no exception. Although there have been efforts to address issues of diversity, equity, and inclusion (DEI) in our own field, gaps persist. To address these gaps, the members of the Diversity, Equity, and Inclusion Advisory Group (DEI-AG) of the American Thoracic Society Pediatrics Assembly created and distributed a Needs Assessment Survey in the United States and Canada to better understand the racial and ethnic demographics of the pediatric pulmonary workforce and to learn more about successes, gaps, and opportunities to enhance how we recruit, train, and retain a diverse workforce. The DEI-AG leadership cochairs convened a workshop to review the findings of the DEI Needs Assessment Survey and to develop strategies to improve the recruitment and retention of URiM fellows and faculty. This Official ATS Workshop Report aims to identify barriers and opportunities for recruitment, training, and career development within the field of pediatric pulmonology. Additionally, we offer useful strategies and resources to improve the recruitment of URiM residents, the mentorship of trainees and junior faculty, and the career development of URiM faculty in academic centers. This Workshop Report is an important first deliverable by the DEI-AG. We hope that this work, originating from within the Pediatrics Assembly, will serve as a model for other Assemblies, disciplines across the ATS, and other fields in Pediatrics.

Health inequities in the modulator era.

PURPOSE OF REVIEW: To discuss the existing health inequities in people with cystic fibrosis (CF) and how the recent development of cystic fibrosis transmembrane regulator (CFTR) modulators may impact these inequities. RECENT FINDINGS: People with CF (pwCF) from low socioeconomic status (SES) have more pulmonary exacerbations, worse nutritional status, lower pulmonary function, and an increased mortality rate with less access to lung transplantation. pwCF who identify as racial and ethnic minorities have earlier mortality, lower lung function, are less likely to be detected on newborn screening resulting in a delayed diagnosis, are underrepresented in clinic trials, and less likely to be eligible for a CFTR modulator. Female sex is associated with more pulmonary exacerbations and earlier mortality. Sexual gender minorities are a vulnerable population with worse health outcomes, and more research is needed in CF. CFTR modulators are inaccessible to low to middle-income countries due to significant cost burden. SUMMARY: People with CF from low SES, racial and ethnic minorities, female sex, and sexual gender minorities face health inequities. CFTR modulator use will further widen existing health inequities given the unequal access to modulators based on nonqualifying genetics and exorbitant cost restricting use both on an individual and global level.

The US national registry for childhood interstitial and diffuse lung disease: Report of study design and initial enrollment cohort.

INTRODUCTION: Childhood interstitial and diffuse lung disease (chILD) encompasses a broad spectrum of rare disorders. The Children's Interstitial and Diffuse Lung Disease Research Network (chILDRN) established a prospective registry to advance knowledge regarding etiology, phenotype, natural history, and management of these disorders. METHODS: This longitudinal, observational, multicenter registry utilizes single-IRB reliance agreements, with participation from 25 chILDRN centers across the U.S. Clinical data are collected and managed using the Research Electronic Data Capture (REDCap) electronic data platform. RESULTS: We report the study design and selected elements of the initial Registry enrollment cohort, which includes 683 subjects with a broad range of chILD diagnoses. The most common diagnosis reported was neuroendocrine cell hyperplasia of infancy, with 155 (23%) subjects. Components of underlying disease biology were identified by enrolling sites, with cohorts of interstitial fibrosis, immune dysregulation, and airway disease being most commonly reported. Prominent morbidities affecting enrolled children included home supplemental oxygen use (63%) and failure to thrive (46%). CONCLUSION: This Registry is the largest longitudinal chILD cohort in the United States to date, providing a powerful framework for collaborating centers committed to improving the understanding and treatment of these rare disorders.

The upper airway microbiome in Hispanic children with cystic fibrosis.

BACKGROUND: Hispanic people with cystic fibrosis (CF) have decreased life expectancy and earlier acquisition of Pseudomonas aeruginosa compared to non-Hispanic white individuals with CF. Racial and ethnic differences in the airway microbiome of CF may contribute to known health disparity, but have not been studied. The objective was to describe differences in the upper airway microbial community in Hispanic and non-Hispanic white children with CF. METHODS: This prospective, observational cohort study of 59 Hispanic and non-Hispanic white children with CF, ages 2-10 years old, was performed at Texas Children's Hospital (TCH) from February 2019 to January 2020. Oropharyngeal swabs were collected from the cohort during clinic visit. Swab samples underwent sequencing (16S V4 rRNA), diversity analysis, and taxonomic profiling. Key demographic and clinical data were collected from the electronic medical record and the CF Foundation Patient Registry (CFFPR). Statistical analysis compared sequencing, demographic, and clinical data. RESULTS: We found no significant difference in Shannon diversity or relative abundance of bacterial phyla between Hispanic and non-Hispanic children with CF. However, a low abundant taxa- "uncultured bacterium" belonging to the order Saccharimonadales was significantly higher in Hispanic children (mean relative abundance = 0.13%) compared to the non-Hispanic children (0.03%). Hispanic children had increased incidence of P. aeruginosa (p = 0.045) compared to non-Hispanic children. CONCLUSION: We did not find a significant difference in the airway microbial diversity between Hispanic and non-Hispanic white children with CF. However, we found a greater relative abundance of Saccharimonadales and higher incidence of P. aeruginosa in Hispanic children with CF.

Detection and identification of fungi in the lower airway of children with and without cystic fibrosis.

Introduction: Airway infection and inflammation lead to the progression of obstructive lung disease in persons with cystic fibrosis (PWCF). However, cystic fibrosis (CF) fungal communities, known drivers of CF pathophysiology, remain poorly understood due to the shortcomings of traditional fungal culture. Our objective was to apply a novel small subunit rRNA gene (SSU-rRNA) sequencing approach to characterize the lower airway mycobiome in children with and without CF. Methods: Bronchoalveolar lavage fluid (BALF) samples and relevant clinical data were collected from pediatric PWCF and disease control (DC) subjects. Total fungal load (TFL) was measured using quantitative PCR, and SSU-rRNA sequencing was used for mycobiome characterization. Results were compared across groups, and Morisita-Horn clustering was performed. Results: 161 (84%) of the BALF samples collected had sufficient load for SSU-rRNA sequencing, with amplification being more common in PWCF. BALF from PWCF had increased TFL and increased neutrophilic inflammation compared to DC subjects. PWCF exhibited increased abundance of Aspergillus and Candida, while Malassezia, Cladosporium, and Pleosporales were prevalent in both groups. CF and DC samples showed no clear differences in clustering when compared to each other or to negative controls. SSU-rRNA sequencing was used to profile the mycobiome in pediatric PWCF and DC subjects. Notable differences were observed between the groups, including the abundance of Aspergillus and Candida. Discussion: Fungal DNA detected in the airway could represent a combination of pathogenic fungi and environmental exposure (e.g., dust) to fungus indicative of a common background signature. Next steps will require comparisons to airway bacterial communities.

At-home end-tidal carbon dioxide measurement in children with invasive home mechanical ventilation.

BACKGROUND: Carbon dioxide concentration trending is used in chronic management of children with invasive home mechanical ventilation (HMV) in clinical settings, but options for end-tidal carbon dioxide (EtCO2 ) monitoring at home are limited. We hypothesized that a palm-sized, portable endotracheal capnograph (PEC) that measures EtCO2 could be adapted for in-home use in children with HMV. METHODS: We evaluated the internal consistency of the PEC by calculating an intraclass correlation coefficient of three back-to-back breaths by children (0-17 years) at baseline health in the clinic. Pearson's correlation was calculated for PEC EtCO2 values with concurrent mean values of in-clinic EtCO2 and transcutaneous CO2 (TCM) capnometers. The Bland-Altman test determined their level of agreement. Qualitative interviews and surveys assessed usability and acceptability by family-caregivers at home. RESULTS: CO2 values were collected in awake children in varied activity levels and positions (N = 30). The intraclass correlation coefficient for the PEC was 0.95 (p < 0.05). The correlation between the PEC and in-clinic EtCO2 device was 0.85 with a mean difference of -3.8 mmHg and precision of ±1.1 mmHg. The correlation between the PEC and the clinic TCM device was 0.92 with a mean difference of 0.2 mmHg and precision of ±1.0. Family-caregivers (N = 10) trialed the PEC at home; all were able to obtain measurements at home while children were awake and sometimes asleep. CONCLUSIONS: A portable, noninvasive device for measuring EtCO2 was feasible and acceptable, with values that trend similarly to currently in-practice, outpatient models. These devices may facilitate monitoring of EtCO2 at home in children with invasive HMV.

Network Analysis to Identify Multi-Omic Correlations in the Lower Airways of Children With Cystic Fibrosis.

The leading cause of morbidity and mortality in cystic fibrosis (CF) is progressive lung disease secondary to chronic airway infection and inflammation; however, what drives CF airway infection and inflammation is not well understood. By providing a physiological snapshot of the airway, metabolomics can provide insight into these processes. Linking metabolomic data with microbiome data and phenotypic measures can reveal complex relationships between metabolites, lower airway bacterial communities, and disease outcomes. In this study, we characterize the airway metabolome in bronchoalveolar lavage fluid (BALF) samples from persons with CF (PWCF) and disease control (DC) subjects and use multi-omic network analysis to identify correlations with the airway microbiome. The Biocrates targeted liquid chromatography mass spectrometry (LC-MS) platform was used to measure 409 metabolomic features in BALF obtained during clinically indicated bronchoscopy. Total bacterial load (TBL) was measured using quantitative polymerase chain reaction (qPCR). The Qiagen EZ1 Advanced automated extraction platform was used to extract DNA, and bacterial profiling was performed using 16S sequencing. Differences in metabolomic features across disease groups were assessed univariately using Wilcoxon rank sum tests, and Random forest (RF) was used to identify features that discriminated across the groups. Features were compared to TBL and markers of inflammation, including white blood cell count (WBC) and percent neutrophils. Sparse supervised canonical correlation network analysis (SsCCNet) was used to assess multi-omic correlations. The CF metabolome was characterized by increased amino acids and decreased acylcarnitines. Amino acids and acylcarnitines were also among the features most strongly correlated with inflammation and bacterial burden. RF identified strong metabolomic predictors of CF status, including L-methionine-S-oxide. SsCCNet identified correlations between the metabolome and the microbiome, including correlations between a traditional CF pathogen, Staphylococcus, a group of nontraditional taxa, including Prevotella, and a subnetwork of specific metabolomic markers. In conclusion, our work identified metabolomic characteristics unique to the CF airway and uncovered multi-omic correlations that merit additional study.

Primary Ciliary Dyskinesia: A Rare and Often Underdiagnosed Disease.

Primary ciliary dyskinesia (PCD) is a rare autosomal recessive disease with clinical features of ear, sinus, and pulmonary infections that overlap with common respiratory illnesses of childhood. It is a progressive disorder that has significant influence on quality of life, lung function, and survival. Given the considerable overlap of symptoms between common illnesses and PCD, a high index of suspicion by primary care providers is needed to consider the diagnosis. There is not a single "gold standard" diagnostic test for PCD and multiple diagnostic methods coupled with specialized expertise is often needed to make the diagnosis. Patients with PCD also have comorbidities requiring a multidisciplinary approach for optimal clinical management. It is important for primary care physicians to recognize the PCD clinical phenotype and have a diagnostic framework for these patients. [Pediatr Ann. 2022;51(2):e82-e85.].

Divergence of bacterial communities in the lower airways of CF patients in early childhood.

RATIONALE: Chronic airway infection and inflammation resulting in progressive, obstructive lung disease is the leading cause of morbidity and mortality in cystic fibrosis. Understanding the lower airway microbiota across the ages can provide valuable insight and potential therapeutic targets. OBJECTIVES: To characterize and compare the lower airway microbiota in cystic fibrosis and disease control subjects across the pediatric age spectrum. METHODS: Bronchoalveolar lavage fluid samples from 191 subjects (63 with cystic fibrosis) aged 0 to 21 years were collected along with relevant clinical data. We measured total bacterial load using quantitative polymerase chain reaction and performed 16S rRNA gene sequencing to characterize bacterial communities with species-level sensitivity for select genera. Clinical comparisons were investigated. MEASUREMENTS AND MAIN RESULTS: Cystic fibrosis samples had higher total bacterial load and lower microbial diversity, with a divergence from disease controls around 2-5 years of age, as well as higher neutrophilic inflammation relative to bacterial burden. Cystic fibrosis samples had increased abundance of traditional cystic fibrosis pathogens and decreased abundance of the Streptococcus mitis species group in older subjects. Interestingly, increased diversity in the heterogeneous disease controls was independent of diagnosis and indication. Sequencing was more sensitive than culture, and antibiotic exposure was more common in disease controls, which showed a negative relationship with load and neutrophilic inflammation. CONCLUSIONS: Analysis of lower airway samples from people with cystic fibrosis and disease controls across the ages revealed key differences in airway microbiota and inflammation. The divergence in subjects during early childhood may represent a window of opportunity for intervention and additional study.

Management of chronic pulmonary disease in the time of coronavirus disease 2019.

PURPOSE OF REVIEW: The purpose of this review is to discuss the most recent data describing the impact of coronavirus disease 2019 (COVID-19) on the pediatric population with chronic pulmonary disease. We specifically focus on children with asthma, cystic fibrosis (CF), and lung transplant recipients. RECENT FINDINGS: Children with asthma, CF, and lung transplant recipients do not appear to have an increased risk of morbidity or mortality with COVID-19 infection compared to the general pediatric population. Data does not support the change or withdrawal of any asthma or CF maintenance medications; however, does advocate for the cessation of aerosolized medications whenever possible to minimize transmission risk. It may not be necessary to adjust immunosuppressive therapy when managing COVID-19 in pediatric lung transplant patients. Mechanisms of infection in airway epithelial cells in children may differ from adults, resulting in a milder phenotype. SUMMARY: Current data about pediatric patients with chronic lung disease infected with severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) is promising but remains scarce. Additional study is needed to definitively understand the complex interplay of the SARS-CoV-2 virus in the airway of children with chronic lung disease, how it differs from adults, and how best to manage the symptoms of acute infection.

Rates of adverse and serious adverse events in children with cystic fibrosis.

BACKGROUND: Cystic fibrosis (CF) is an autosomal recessive disease characterized by chronic sinopulmonary symptoms and chronic gastrointestinal symptoms that begins in infancy. Children with CF are increasingly being included in clinical trials. In order to fully evaluate the impact of new therapies in future clinical trials, an understanding of baseline adverse event (AE) rates in children with CF is needed. To address this, we determined the rates of common AEs in pediatric patients with CF who participated in two clinical trials. METHODS: We reviewed AEs for placebo recipients in the AZ0004 study and inhaled tobramycin recipients in the Early Pseudomonas Infection Control (EPIC) clinical trial. AEs were categorized based on Medical Dictionary for Regulatory Activities (MedDRA) coding classifications and pooled into common, batched AE descriptors. AE rates were estimated from negative binomial models according to age groups, severity of lung disease, and season. RESULTS: A total of 433 children had 8,266 total AEs reported, or 18.1 (95% CI 17.0, 19.2) AEs per person per year. Respiratory AEs were the most commonly reported AEs, with a rate of 7.6 events per person-year. The total SAE rate was 0.33 per person per-year. Cough was the most commonly reported respiratory AE, with 61% of subjects reporting at least one episode of cough within 4 months. The rate ratio of any AE was higher in Spring, Fall, and Winter, compared with Summer. CONCLUSIONS: AEs occur commonly in pediatric CF clinical trial participants. Season of enrollment could affect AE rates.

Preferences for disclosing adverse childhood experiences for children and adults with cystic fibrosis.

INTRODUCTION: The 2017-2018 National Survey of Children's Health estimates that 30 million (42%) US children have experienced at least one adverse childhood experience (ACE), including abuse, neglect, and household dysfunction. ACEs negatively impact long-term health, and there has been no study of ACEs in cystic fibrosis (CF). We assessed willingness to disclose ACEs experienced by children with CF by surveying their parents and adults with CF. METHODS: We anonymously surveyed parents of children with CF and adults with CF at the Northwestern University/Lurie Children's CF Center to determine their willingness to disclose ACEs. RESULTS: The survey was completed by 46/157 (29%) parents and 36/105 (34%) adults with CF. Few parents (22%) and adults (17%) were willing to discuss most or all specific ACEs, more were willing to disclose the number of ACEs experienced in a category (57% parents, 47% adults), and the majority were willing to participate in anonymous research about ACEs (76% parents, 67% adults). Most parents (63%) and adults (50%) would prefer to have ACEs screened separately from their CF appointment, and most parents (63%) and adults (56%) wanted to learn more about ACEs from a member of their care team. CONCLUSIONS: Participants preferred to disclose the number of categorical ACEs rather than specific ACEs and most were open to participating in anonymous ACEs research. More research is needed before implementing screening. Educating patients, parents, and providers about ACEs and appropriate interventions when ACES are identified is needed for both research and clinical applications of ACEs screening.

Cystic fibrosis diagnosed by state newborn screening: Or is it?

Newborn screening for cystic fibrosis is universal across the United States; however, each state chooses the method by which they screen. Illinois employs a two-step process which includes the measurement of the immunoreactive trypsinogen followed by an assay designed to detect 74 of the most common genetic mutations in the cystic fibrosis transmembrane conductance regulator protein. We report the case of an infant born in Illinois with a positive cystic fibrosis newborn screening with an elevated immunoreactive trypsinogen and two genetic mutations identified (F508del/F508del). The primary care physician informed the parents their child had cystic fibrosis and referred her for a confirmatory sweat test which was negative for cystic fibrosis. Upon further investigation, the assay was found to have been set up incorrectly and repeat analysis identified the genotype F508del/F508C. This case highlights the importance of performing the confirmatory sweat test prior to making a diagnosis of cystic fibrosis.

A proposal for the addressing the needs of the pediatric pulmonary work force.

Unprecedented opportunities and daunting difficulties are anticipated in the future of pediatric pulmonary medicine. To address these issues and optimize pediatric pulmonary training, a group of faculty from various institutions met in 2019 and proposed specific, long-term solutions to the emerging problems in the field. Input on these ideas was then solicited more broadly from faculty with relevant expertise and from recent trainees. This proposal is a synthesis of these ideas. Pediatric pulmonology was among the first pediatric specialties to be grounded deliberately in science, requiring its fellows to demonstrate expertise in scientific inquiry (1). In the future, we will need more training in science, not less. Specifically, the scope of scientific inquiry will need to be broader. The proposal outlined below is designed to help optimize the practices of current providers and to prepare the next generation to be leaders in pediatric care in the future. We are optimistic that this can be accomplished. Our broad objectives are (a) to meet the pediatric subspecialty workforce demand by increasing interest and participation in pediatric pulmonary training; (b) to modernize training to ensure that future pediatric pulmonologists will be prepared clinically and scientifically for the future of the field; (c) to train pediatric pulmonologists who will add value in the future of pediatric healthcare, complemented by advanced practice providers and artificial intelligence systems that are well-informed to optimize quality healthcare delivery; and (d) to decrease the cost and improve the quality of care provided to children with respiratory diseases.

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.