Prevalence, stability, and clinical significance of an isolated low FEV1 spirometry pattern in children.

OBJECTIVES: In adults, an isolated low FEV1 pattern (an FEV1 below the lower limit of normal with a preserved FVC and FEV1/FVC) has been associated with the risk of developing airway obstruction. Our objective was to examine the prevalence, stability, and clinical significance of an isolated low FEV1 pattern in the pediatric population. METHODS: We conducted a retrospective study of spirometries from children ages 6-21 years and categorized tests into spirometry patterns according to published guidelines and recent literature. In a subgroup of tests with an isolated low FEV1 pattern, we evaluated spirometry technique. We also examined the association of having a test with an isolated low FEV1 pattern with clinical markers of disease severity in a subgroup of children with cystic fibrosis (CF). RESULTS: The isolated low FEV1 pattern was uncommon across the 29,979 tests included (n = 645 [2%]). In the 263 children with an isolated low FEV1 pattern who had a follow-up test performed, the most frequent spirometry pattern at last test was normal (n = 123 [47%]). A primary diagnosis of CF was associated with increased odds of having at least one test with an isolated low FEV1 pattern (OR = 8.37, 95% CI = 4.70-15.96, p < .001). The spirometry quality in a subgroup of tests with an isolated low FEV1 pattern (n = 50) was satisfactory. In the subgroup of children with CF (n = 102), those who had a test with an isolated low FEV1 pattern had higher odds of using oral antibiotics in the last 12 months than those who had a normal pattern (OR = 3.50, 95% CI = 1.15-10.63, p = .03). CONCLUSIONS: The isolated low FEV1 pattern can occur repeatedly over time, usually transitions to a normal pattern, is not due to a poor spirometry technique, and could be clinically relevant in children with chronic lung diseases.

Gilbert's syndrome leads to elevated bilirubin after initiation of elexacaftor/tezacaftor/ivacaftor in people with cystic fibrosis.

Nine people with cystic fibrosis (pwCF) were found to have isolated elevations in serum total bilirubin after starting elexacaftor/tezacaftor/ivacaftor (ETI) that were associated with Gilbert's Syndrome. In longitudinal examination, total bilirubin levels increased substantially after initiation of ETI without elevations in liver transaminases in those with this syndrome. Because elevated bilirubin levels in Gilbert's Syndrome are benign, ETI was able to be continued in these individuals. Genetic testing for this relatively common syndrome should be strongly considered for pwCF experiencing isolated hyperbilirubinemia after starting ETI, since appropriate diagnosis may help pwCF avoid unnecessary interruption in this therapy with significant health benefits in CF.

Longitudinal profiling of the intestinal microbiome in children with cystic fibrosis treated with elexacaftor-tezacaftor-ivacaftor.

The intestinal microbiome influences growth and disease progression in children with cystic fibrosis (CF). Elexacaftor-tezacaftor-ivacaftor (ELX/TEZ/IVA), the newest pharmaceutical modulator for CF, restores the function of the pathogenic mutated CF transmembrane conductance regulator (CFTR) channel. We performed a single-center longitudinal analysis of the effect of ELX/TEZ/IVA on the intestinal microbiome, intestinal inflammation, and clinical parameters in children with CF. Following ELX/TEZ/IVA, children with CF had significant improvements in body mass index and percent predicted forced expiratory volume in one second, and required fewer antibiotics for respiratory infections. Intestinal microbiome diversity increased following ELX/TEZ/IVA coupled with a decrease in the intestinal carriage of Staphylococcus aureus, the predominant respiratory pathogen in children with CF. There was a reduced abundance of microbiome-encoded antibiotic resistance genes. Microbial pathways for aerobic respiration were reduced after ELX/TEZ/IVA. The abundance of microbial acid tolerance genes was reduced, indicating microbial adaptation to increased CFTR function. In all, this study represents the first comprehensive analysis of the intestinal microbiome in children with CF receiving ELX/TEZ/IVA.IMPORTANCECystic fibrosis (CF) is an autosomal recessive disease with significant gastrointestinal symptoms in addition to pulmonary complications. Recently approved treatments for CF, CF transmembrane conductance regulator (CFTR) modulators, are anticipated to substantially improve the care of people with CF and extend their lifespans. Prior work has shown that the intestinal microbiome correlates with health outcomes in CF, particularly in children. Here, we study the intestinal microbiome of children with CF before and after the CFTR modulator, ELX/TEZ/IVA. We identify promising improvements in microbiome diversity, reduced measures of intestinal inflammation, and reduced antibiotic resistance genes. We present specific bacterial taxa and protein groups which change following ELX/TEZ/IVA. These results will inform future mechanistic studies to understand the microbial improvements associated with CFTR modulator treatment. This study demonstrates how the microbiome can change in response to a targeted medication that corrects a genetic disease.

The relationship between the intestinal microbiome and body mass index in children with cystic fibrosis.

BACKGROUND: The nutritional status of children with cystic fibrosis (CF), as assessed by their body mass index percentile (BMIp), is a critical determinant of long-term health outcomes. While the intestinal microbiome plays an important role in nutrition, little is known regarding the relationship of the microbiome and BMIp in children with CF. METHODS: Pediatric patients (< 18 years old) with CF and healthy comparison patients (HCs) were enrolled in the study and stool samples obtained. BMIp was categorized as Green Zone (BMIp > 50th), Yellow Zone (BMIp 25th-49th) and Red Zone (BMIp < 25th). Intestinal microbiome assessment was performed via 16S rRNA gene sequencing; microbial richness, diversity, and differential species abundance were assessed. RESULTS: Stool samples were collected from 107 children with CF and 50 age-matched HCs. Compared to HCs, children with CF were found to have lower bacterial richness, alpha-diversity, and a different microbial composition. When evaluating them by their BMIp color zone, richness and alpha-diversity were lowest in those in the Red Zone. In addition, an unclassified amplicon sequence variant (ASV) of Blautia, a known butyrate-producing anaerobe, was of lowest abundance in children in the Red Zone. CONCLUSION: Children with CF have a dysbiotic intestinal microbiome with specific changes that accompany changes in BMIp. Longitudinal assessments of the microbiome and its metabolic activities over time are needed to better understand how improvements in the microbiome may improve nutrition and enhance long-term survival in children with CF.

Longitudinal Profiling of the Intestinal Microbiome in Children with Cystic Fibrosis Treated with Elexacaftor-Tezacaftor-Ivacaftor.

The intestinal microbiome influences growth and disease progression in children with cystic fibrosis (CF). Elexacaftor-tezacaftor-ivacaftor (ELX/TEZ/IVA), the newest pharmaceutical modulator for CF, restores function of the pathogenic mutated CFTR channel. We performed a single-center longitudinal analysis of the effect of ELX/TEZ/IVA on the intestinal microbiome, intestinal inflammation, and clinical parameters in children with CF. Following ELX/TEZ/IVA, children with CF had significant improvements in BMI, ppFEV1 and required fewer antibiotics for respiratory infections. Intestinal microbiome diversity increased following ELX/TEZ/IVA coupled with a decrease in the intestinal carriage of Staphylococcus aureus, the predominant respiratory pathogen in children with CF. There was a reduced abundance of microbiome-encoded antibiotic-resistance genes. Microbial pathways for aerobic respiration were reduced after ELX/TEZ/IVA. The abundance of microbial acid tolerance genes was reduced, indicating microbial adaptation to increased CFTR function. In all, this study represents the first comprehensive analysis of the intestinal microbiome in children with CF receiving ELX/TEZ/IVA.

Prevalence, Risk Factors, and Sequelae of Asymptomatic Clostridioides difficile Colonization in Children with Cystic Fibrosis.

Patients with CF (pwCF) have high antibiotic use and an altered intestinal microbiome, known risk factors for infection with Clostridioides difficile. However, in adults with CF, C. difficile infection (CDI) is uncommon and asymptomatic colonization with C. difficile occurs frequently, for reasons that remain unclear. We investigated the rate, risk factors, and sequelae of asymptomatic C. difficile colonization in children with CF (cwCF). We identified that 32% of cwCF were colonized with C. difficile without acute gastrointestinal symptoms. Higher BMI and exposure to specific antibiotic classes (cephalosporins, fluoroquinolones, and vancomycin) were significantly associated with C. difficile colonization. No children developed symptomatic CDI in 90-days following enrollment.

Sleep screening for cystic fibrosis patients: A survey of cystic fibrosis programs.

OBJECTIVE: The prevalence of sleep disorders in patients with cystic fibrosis (CF) is unknown, and no standardized screening or treatment guidelines exist to address sleep disorders in CF. The objective of this study is to characterize current sleep screening practices in adult, pediatric, combined, and affiliate CF programs. METHODS: A survey was developed in Research Electronic Data Capture and distributed to program directors of accredited CF programs in the United States. RESULTS: Eighty-eight program directors responded (36% adult, 43% pediatric, 16% combined, 3% affiliate, and 1% unidentified). Of the respondents, 68% were part of an academic institution, 24% were associated with an academic institution, and 8% were part of a community or private program. Program sizes ranged from less than 50 to more than 500 patients. Routine or informal sleep screening was not performed in 44% of adults, 29% of pediatricians, and 35% of combined and affiliate programs. Most programs (>80%) have access to otolaryngology and sleep medicine although not all of these programs refer patients for evaluation of sleep disorders. Most program directors (77%) perceive sleep disorders as a problem in CF and would recommend routine sleep screening. Possible barriers to sleep screening included clinic flow, screening fatigue, and lack of recommendations for sleep screening. CONCLUSIONS: Formal sleep screening is inconsistent among CF care centers although most survey respondents would recommend the inclusion of screening in routine CF care. Future work is needed to further evaluate the impact of sleep disorders in CF and determine best practices for standardization of sleep screening and treatment.

Chronic rhino-sinusitis treatment in children with cystic fibrosis: A cross-sectional survey of pediatric pulmonologists and otolaryngologists.

OBJECTIVES: Children with cystic fibrosis (CF) have a high incidence of chronic rhinosinusitis (CRS); however, no clinical care guidelines currently exist for the management of CRS in these patients. As a result, there is variation in the treatment of CRS in children, especially when it comes to the frequency of surgery for nasal polyposis. METHODS: A 28-question survey was sent to pediatric otolaryngologists (POs) and pulmonologists (PPs) who care for pediatric CF patients. Questions assessed the level of agreement that practitioners had with various approaches to CRS care in pediatric CF patients. RESULTS: Responses from 114 POs and 50 PPs were included in our final analysis. Each group demonstrated significantly different approaches to the medical and surgical management of CRS in pediatric CF patients. POs prefer multi-modal approach while PPs prefer single-modal approaches. With respect to medical management, PPs incline towards IV antibiotics while POs tend toward oral steroids. CONCLUSION: POs and PPs strongly agree that CRS has an impact on overall disease state and quality of life of pediatric CF patients. However, POs and PPs significantly differ in their approach to treating CRS, demonstrating a potential need for clinical care guidelines for the management these common sequelae of CF.

Evaluating the sinus and Nasal Quality of Life Survey in the pediatric cystic fibrosis patient population.

INTRODUCTION: The Sinus and Nasal Quality of Life Survey (SN-5) is a validated quality of life (QOL) questionnaire for chronic rhinosinusitis in patients age 2-12. Its utility in the cystic fibrosis (CF) has been studied, but not yet validated. The purpose of this study is to determine the effectiveness of the SN-5 for evaluation of sinonasal symptoms in the pediatric CF population. METHODS: This retrospective study analyzed SN-5 surveys completed between 2012 and 2015 by pediatric CF patients and caregivers. Baseline and follow-up overall QOL scores and specific symptom scores were obtained from surveys completed in the three-year span. Non-parametric statistics were conducted to identify differences in survey data. RESULTS: A total of 165 patients completed baseline and follow-up surveys. The overall QOL of the patient cohort did not change over the duration of the study (p = 0.660). Thirty-seven patients indicated higher overall QOL, with all five symptom scores showing significant improvement. Analysis by age group showed that QOL was significantly correlated with all five symptoms for children ages 0-4. In patients 5-12 years, overall QOL was only correlated with sinus infection (r = -0.3090, p = 0.01). QOL was significantly correlated with sinus infection (r = -0.2903, p = 0.04) and allergy symptoms (r = -0.5644, p < 0.01) in patients >12 years of age. CONCLUSION: There remains a need for a validated CRS QOL tool for children with CF. Though the SN-5 has previously been described as a potential instrument, our data suggest that it may be more valuable in children ages 0-4.

Elevated prostaglandin E metabolites and abnormal plasma fatty acids at baseline in pediatric cystic fibrosis patients: a pilot study.

BACKGROUND: Airway inflammation is a significant contributor to the morbidity of cystic fibrosis (CF) disease. One feature of this inflammation is the production of oxygenated metabolites, such as prostaglandins. Individuals with CF are known to have abnormal metabolism of fatty acids, typically resulting in reduced levels of linoleic acid (LA) and docosahexaenoic acid (DHA). METHODS: This is a randomized, double-blind, cross-over clinical trial of DHA supplementation with endpoints of plasma fatty acid levels and prostaglandin E metabolite (PGE-M) levels. Patients with CF age 6-18 years with pancreatic insufficiency were recruited. Each participant completed 3 four-week study periods: DHA at two different doses (high dose and low dose) and placebo with a minimum 4 week wash-out between each period. Blood, urine, and exhaled breath condensate (EBC) were collected at baseline and after each study period for measurement of plasma fatty acids as well as prostaglandin E metabolites. RESULTS: Seventeen participants were enrolled, and 12 participants completed all 3 study periods. Overall, DHA supplementation was well tolerated without significant adverse events. There was a significant increase in plasma DHA levels with supplementation, but no significant change in arachidonic acid (AA) or LA levels. However, at baseline, AA levels were lower and LA levels were higher than previously reported for individuals with CF. Urine PGE-M levels were elevated in the majority of participants at baseline, and while levels decreased with DHA supplementation, they also decreased with placebo. CONCLUSIONS: Urine PGE-M levels are elevated at baseline in this cohort of pediatric CF patients, but there was no significant change in these levels with DHA supplementation compared to placebo. In addition, baseline plasma fatty acid levels for this cohort showed some difference to prior reports, including higher levels of LA and lower levels of AA, which may reflect changes in clinical care, and consequently warrants further investigation.

A facilitated peer mentoring program for junior faculty to promote professional development and peer networking.

PURPOSE: To explore the design, implementation, and efficacy of a faculty development program in a cohort of early career junior faculty. METHOD: Interested junior faculty members were divided into interdisciplinary small groups led by senior faculty facilitators. The groups met monthly for 1.5 hours to review a modular curriculum from 2011 to 2013. Using a survey at two time points (September 2011 and 2013) and an interim program evaluation, the authors collected data on participants' demographics, faculty interconnectedness, and self-reported knowledge, skills, and attitudes (KSA) in the domains of professional development and scholarship, including the ability to write career goals and align activities with those goals. RESULTS: A total of 104 junior faculty participated in the program. They demonstrated changes in self-reported KSA in the domains of professional development (P = .013, P = .001) and scholarship (P = .038, P = .015) with an increase in ability to write career goals (P < .001), ability to align activities with those goals (P < .001), and number of and amount of time spent pursuing activities related to those goals (P = .022). These changes were more significant among female faculty and were not affected by academic rank or time since last training. Interconnectedness among faculty increased during the period of study-the number of nodes and ties between nodes within the network increased. CONCLUSIONS: This facilitated peer mentoring program for junior faculty was effective in improving the KSA necessary to promote early career advancement and peer networking, especially for women.

Transition care for children with special health care needs.

BACKGROUND: Approximately 750,000 children in the United States with special health care needs will transition from pediatric to adult care annually. Fewer than half receive adequate transition care. METHODS: We had conversations with key informants representing clinicians who provide transition care, pediatric and adult providers of services for individuals with special health care needs, policy experts, and researchers; searched online sources for information about currently available programs and resources; and conducted a literature search to identify research on the effectiveness of transition programs. RESULTS: We identified 25 studies evaluating transition care programs. Most (n = 8) were conducted in populations with diabetes, with a smaller literature (n = 5) on transplant patients. We identified an additional 12 studies on a range of conditions, with no more than 2 studies on the same condition. Common components of care included use of a transition coordinator, a special clinic for young adults in transition, and provision of educational materials. CONCLUSIONS: The issue of how to provide transition care for children with special health care needs warrants further attention. Research needs are wide ranging, including both substantive and methodologic concerns. Although there is widespread agreement on the need for adequate transition programs, there is no accepted way to measure transition success. It will be essential to establish consistent goals to build an adequate body of literature to affect practice.

Childhood interstitial lung diseases: an 18-year retrospective analysis.

OBJECTIVE: Childhood interstitial lung diseases (ILD) occur in a variety of clinical contexts. Advances in the understanding of disease pathogenesis and use of standardized terminology have facilitated increased case ascertainment. However, as all studies have been performed at specialized referral centers, the applicability of these findings to general pulmonary practice has been uncertain. The objective of this study was to determine the historical occurrence of childhood ILD to provide information reflecting general pediatric pulmonary practice patterns. METHODS: Childhood ILD cases seen at Vanderbilt Children's Hospital from 1994 to 2011 were retrospectively reviewed and classified according to the current pediatric diffuse lung disease histopathologic classification system. RESULTS: A total of 93 cases were identified, of which 91.4% were classifiable. A total of 68.8% (64/93) of subjects underwent lung biopsy in their evaluations. The largest classification categories were disorders related to systemic disease processes (24.7%), disorders of the immunocompromised host (24.7%), and disorders more prevalent in infancy (22.6%). Eight cases of neuroendocrine cell hyperplasia of infancy (NEHI) were identified, including 5 that were previously unrecognized before this review. CONCLUSIONS: Our findings demonstrate the general scope of childhood ILD and that these cases present within a variety of pediatric subspecialties. Retrospective review was valuable in recognizing more recently described forms of childhood ILD. As a significant portion of cases were classifiable based on clinical, genetic, and/or radiographic criteria, we urge greater consideration to noninvasive diagnostic approaches and suggest modification to the current childhood ILD classification scheme to accommodate the increasing number of cases diagnosed without lung biopsy.

Non-physician providers as clinical providers in cystic fibrosis: survey of U.S. programs.

BACKGROUND AND METHODS: Non-physician providers (NPPs) including nurse practitioners (NPs) and physician assistants (PAs) are important members of CF care teams, but limited data exist about the extent NPPs are involved in CF care. A subcommittee was established by the CF Foundation to gather information about current involvement of NPPs. Surveys were sent to adult, pediatric and affiliate CF program directors (PDs) and NPPs working in US CF programs. RESULTS: Responses were received from 108 PDs (49% pediatric, 34% adult, 17% affiliate). Overall, 53% of the 108 programs had NPPs and 70% had or planned to hire NPPs. Reasons for NPP use included ideal clinical role (75%), expansion of services (72%), and physician shortage (40%). The survey collected 73 responses from NPPs (96% NPs, 4% PAs) who worked in pediatric (49%), adult (29%), affiliate (3%), or multiple programs (19%). Training occurred on the job in 88% and from prior CF experience in 21%. NPPs provided coverage in outpatient clinics (82%), inpatient care (64%), and weekend and/or night call (22%). In addition to clinical roles, NPPs are involved in education (95%), research (81%), and leadership (55%). The major obstacle reported by PDs and NPPs was billing with only 12% of programs reporting NPP salaries covered by billing revenue alone. Salary support included hospital support (67%), billing (39%), center grant (35%), and other grant/contract (25%). NPPs bill for outpatient and inpatient care in 65% and 28% of programs, respectively. CONCLUSIONS: NPPs are working with physicians in many centers and have the potential to help meet the increasing clinical workforce demands. Further evaluation of financial issues is indicated to continue the support of NPP jobs in CF. Roles and expectations need to be clearly defined. Initial and ongoing training standards and opportunities should be explored.