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Background: Elexacaftor–tezacaftor–ivacaftor has been shown to be safe and efficacious in people with cystic fibrosis and at least one F508del allele. Our aim was to identify a novel cystic fibrosis transmembrane conductance regulator (CFTR) modulator combination capable of further increasing CFTR-mediated chloride transport, with the potential for once-daily dosing. Methods: We conducted two phase 2 clinical trials to assess the safety and efficacy of a once-daily combination of vanzacaftor–tezacaftor–deutivacaftor in participants with cystic fibrosis who were aged 18 years or older. A phase 2 randomised, double-blind, active-controlled study (VX18-561-101; April 17, 2019, to Aug 20, 2020) was carried out to compare deutivacaftor monotherapy with ivacaftor monotherapy in participants with CFTR gating mutations, following a 4-week ivacaftor monotherapy run-in period. Participants were randomly assigned to receive either ivacaftor 150 mg every 12 h, deutivacaftor 25 mg once daily, deutivacaftor 50 mg once daily, deutivacaftor 150 mg once daily, or deutivacaftor 250 mg once daily in a 1:1:2:2:2 ratio. The primary endpoint was absolute change in ppFEV1 from baseline at week 12. A phase 2 randomised, double-blind, controlled, proof-of-concept study of vanzacaftor–tezacaftor–deutivacaftor (VX18-121-101; April 30, 2019, to Dec 10, 2019) was conducted in participants with cystic fibrosis and heterozygous for F508del and a minimal function mutation (F/MF genotypes) or homozygous for F508del (F/F genotype). Participants with F/MF genotypes were randomly assigned 1:2:2:1 to receive either 5 mg, 10 mg, or 20 mg of vanzacaftor in combination with tezacaftor–deutivacaftor or a triple placebo for 4 weeks, and participants with the F/F genotype were randomly assigned 2:1 to receive either vanzacaftor (20 mg)–tezacaftor–deutivacaftor or tezacaftor–ivacaftor active control for 4 weeks, following a 4-week tezacaftor–ivacaftor run-in period. Primary endpoints for part 1 and part 2 were safety and tolerability and absolute change in ppFEV1 from baseline to day 29. Secondary efficacy endpoints were absolute change from baseline at day 29 in sweat chloride concentrations and Cystic Fibrosis Questionnaire-Revised (CFQ-R) respiratory domain score. These clinical trials are registered with ClinicalTrials.gov, NCT03911713 and NCT03912233, and are complete. Findings: In study VX18-561-101, participants treated with deutivacaftor 150 mg once daily (n=23) or deutivacaftor 250 mg once daily (n=24) had mean absolute changes in ppFEV1 of 3·1 percentage points (95% CI –0·8 to 7·0) and 2·7 percentage points (–1·0 to 6·5) from baseline at week 12, respectively, versus –0·8 percentage points (–6·2 to 4·7) with ivacaftor 150 mg every 12 h (n=11); the deutivacaftor safety profile was consistent with the established safety profile of ivacaftor 150 mg every 12 h. In study VX18-121-101, participants with F/MF genotypes treated with vanzacaftor (5 mg)–tezacaftor–deutivacaftor (n=9), vanzacaftor (10 mg)–tezacaftor–deutivacaftor (n=19), vanzacaftor (20 mg)–tezacaftor–deutivacaftor (n=20), and placebo (n=10) had mean changes relative to baseline at day 29 in ppFEV1 of 4·6 percentage points (−1·3 to 10·6), 14·2 percentage points (10·0 to 18·4), 9·8 percentage points (5·7 to 13·8), and 1·9 percentage points (−4·1 to 8·0), respectively, in sweat chloride concentration of −42·8 mmol/L (–51·7 to –34·0), −45·8 mmol/L (95% CI –51·9 to –39·7), −49·5 mmol/L (–55·9 to –43·1), and 2·3 mmol/L (−7·0 to 11·6), respectively, and in CFQ-R respiratory domain score of 17·6 points (3·5 to 31·6), 21·2 points (11·9 to 30·6), 29·8 points (21·0 to 38·7), and 3·3 points (−10·1 to 16·6), respectively. Participants with the F/F genotype treated with vanzacaftor (20 mg)–tezacaftor–deutivacaftor (n=18) and tezacaftor–ivacaftor (n=10) had mean changes relative to baseline (taking tezacaftor–ivacaftor) at day 29 in ppFEV1 of 15·9 percentage points (11·3 to 20·6) and −0·1 percentage points (−6·4 to 6·1), respectively, in sweat chloride concentration of −45·5 mmol/L (−49·7 to −41·3) and −2·6 mmol/L (−8·2 to 3·1), respectively, and in CFQ-R respiratory domain score of 19·4 points (95% CI 10·5 to 28·3) and −5·0 points (−16·9 to 7·0), respectively. The most common adverse events overall were cough, increased sputum, and headache. One participant in the vanzacaftor–tezacaftor–deutivacaftor group had a serious adverse event of infective pulmonary exacerbation and another participant had a serious rash event that led to treatment discontinuation. For most participants, adverse events were mild or moderate in severity. Interpretation: Once-daily dosing with vanzacaftor–tezacaftor–deutivacaftor was safe and well tolerated and improved lung function, respiratory symptoms, and CFTR function. These results support the continued investigation of vanzacaftor–tezacaftor–deutivacaftor in phase 3 clinical trials compared with elexacaftor–tezacaftor–ivacaftor. Funding: Vertex Pharmaceuticals.

RATIONALE: People with cystic fibrosis (CF) experience acute worsening of respiratory symptoms and lung function known as pulmonary exacerbations. Treatment with intravenous antimicrobials is common; however, there is scant evidence to support a standard treatment duration. OBJECTIVES: To test differing durations of intravenous antimicrobials for CF exacerbations. METHODS: STOP2 (Standardized Treatment of Pulmonary Exacerbations 2) was a multicenter, randomized, controlled clinical trial in exacerbations among adults with CF. After 7–10 days of treatment, participants exhibiting predefined lung function and symptom improvements were randomized to 10 or 14 days’ total antimicrobial duration; all others were randomized to 14 or 21 days’ duration. MEASUREMENTS AND MAIN RESULTS: The primary outcome was percent predicted FEV(1) (ppFEV(1)) change from treatment initiation to 2 weeks after cessation. Among early responders, noninferiority of 10 days to 14 days was tested; superiority of 21 days compared with 14 days was compared for the others. Symptoms, weight, and adverse events were secondary. Among 982 randomized people, 277 met improvement criteria and were randomized to 10 or 14 days of treatment; the remaining 705 received 21 or 14 days of treatment. Mean ppFEV(1) change was 12.8 and 13.4 for 10 and 14 days, respectively, a ‒0.65 difference (95% CI [‒3.3 to 2.0]), excluding the predefined noninferiority margin. The 21- and 14-day arms experienced 3.3 and 3.4 mean ppFEV(1) changes, a difference of ‒0.10 (‒1.3 to 1.1). Secondary endpoints and sensitivity analyses were supportive. CONCLUSIONS: Among adults with CF with early treatment improvement during exacerbation, ppFEV(1) after 10 days of intravenous antimicrobials is not inferior to 14 days. For those with less improvement after one week, 21 days is not superior to 14 days. Clinical trial registered with www.clinicaltrials.gov (NCT02781610).

BACKGROUND: Cystic fibrosis (CF) is characterized by neutrophilic inflammation in the airways. Leukotriene B4 (LTB4) is a neutrophil chemoattractant and has been implicated in CF pathogenesis. Acebilustat, a novel, synthetic, small-molecule leukotriene A4 hydrolase inhibitor, reduces LTB4 production. We report findings from a randomized placebo-controlled trial of acebilustat in adult subjects with mild-to-moderate lung disease.METHODS: Subjects were randomized (1:1:1) to once-daily acebilustat 50 mg, 100 mg or placebo for 48 weeks, concomitantly with their current therapeutic regimen. Subjects were stratified by use of concomitant CF transmembrane conductance regulator (CFTR) modulators, baseline percent predicted forced expiratory volume in 1 second (ppFEV1) 50-75 and >75, and number of pulmonary exacerbations in the past year (1 or >1). Primary endpoints were the change from baseline in ppFEV1 and safety. Secondary endpoints included the rate of pulmonary exacerbations.RESULTS: Overall, 199 subjects were randomized and dosed (acebilustat 50 mg, n=67; acebilustat 100 mg, n=66; placebo, n=66). Baseline demographics and disease profile were well balanced among treatment groups. Acebilustat had no statistically significant effect on the primary endpoint of change in ppFEV1 at week 48 or the secondary endpoint pulmonary exacerbations. There was a trend towards reduced pulmonary exacerbations in subjects receiving acebilustat in pre-specified populations with ppFEV1>75 (35% rate reduction) and those on concomitant CFTR modulator therapy (20% rate reduction). Acebilustat was well tolerated.CONCLUSIONS: Acebilustat did not improve lung function. A trend towards reduced pulmonary exacerbations in subjects with an earlier stage of lung disease suggests a potential effect in this population.

Summary Background Staphylococcus aureus is the bacterium cultured most often from respiratory secretions of people with cystic fibrosis. Both meticillin-susceptible S aureus and meticillin-resistant S aureus (MRSA) can adapt to form slow-growing, antibiotic-resistant isolates known as small-colony variants that are not routinely identified by clinical laboratories. We aimed to determine the prevalence and clinical significance of S aureus small-colony variants and their subtypes among children with cystic fibrosis. Methods The Small Colony Variant Staphylococcus aureus (SCVSA) study was a 2-year longitudinal study of children aged 6–16 years at five US cystic fibrosis centres, using culture methods sensitive for small-colony variants. Children were eligible if they had a documented diagnosis of cystic fibrosis and a minimum of two cystic fibrosis clinic visits and two respiratory cultures in the previous 12 months at enrolment. Participants attended clinic visits quarterly, at which respiratory tract samples were taken and measures of lung function (percentage of predicted forced expiratory volume in 1 s [FEV1] and frequency of respiratory exacerbations) were recorded. We determined the prevalence of small-colony variants and their subtypes, and assessed their independent associations with lung function and respiratory exacerbations using linear mixed-effects and generalised estimating equation logistic regression models. Analyses included both univariate models (unadjusted) and multivariate models that adjusted for potential confounders, including age, sex, race, baseline microbiology, treatment with CFTR modulator, and CTFR genotype. Findings Between July 1, 2014, and May 26, 2015, we enrolled 230 children. Participants were followed-up for 2 years, with a mean of 6·4 visits (SD 1·14) per participant (range 2–9 visits) and a mean interval between visits of 3·94 months (SD 1·77). Across the 2-year period, S aureus small-colony variants were detected in 64 (28%) participants. Most (103 [56%] of 185) of the small-colony variants detected in these participants were thymidine dependent. Children with small-colony variants had significantly lower mean percentage of predicted FEV1 at baseline than did children without small-colony variants (85·5 [SD 19] vs 92·4 [SD 18·6]; p=0·0145). Small-colony variants were associated with significantly lower percentage of predicted FEV1 throughout the study in regression models, both in univariate analyses (regression coefficient −7·07, 95% CI −12·20 to −1·95; p=0·0068) and in multivariate analyses adjusting for potential confounders (−5·50, −10·51 to −0·48; p=0·0316). Small colony variants of the thymidine-dependent subtype had the strongest association with lung function in multivariate regression models (regression coefficient −10·49, −17·25 to −3·73; p=0·0024). Compared with children without small-colony variants, those with small-colony variants had significantly increased odds of respiratory exacerbations in univariate analyses (odds ratio 1·73, 95% CI 1·19 to 2·52; p=0·0045). Children with thymidine-dependent small-colony variants had significantly increased odds of respiratory exacerbations (2·81, 1·69–4·67; p=0·0001), even after adjusting for age, sex, race, genotype, CFTR modulator, P aeruginosa culture status, and baseline percentage of predicted FEV1 (2·17, 1·33–3·57; p=0·0021), whereas those with non-thymidine-dependent small-colony variants did not. In multivariate models including small-colony variants and MRSA status, P aeruginosa was not independently associated with lung function (regression coefficient −4·77, 95% CI −10·36 to 0·83; p=0·10) and was associated with reduced odds of exacerbations (0·54, 0·36 to 0·81; p=0·0028). Only the small-colony variant form of MRSA was associated with reduced lung function (−8·44, −16·15 to −0·72; p=0·0318) and increased odds of exacerbations (2·15, 1·24 to 3·71; p=0·0061). Interpretation Infection with small-colony variants, and particularly thymidine-dependent small-colony variants, was common in a multicentre paediatric population with cystic fibrosis and associated with reduced lung function and increased risk of respiratory exacerbations. The adoption of small-colony variant identification and subtyping methods by clinical laboratories, and the inclusion of small-colony variant prevalence data in cystic fibrosis registries, should be considered for ongoing surveillance and study. Funding The Cystic Fibrosis Foundation and the National Institutes of Health.

Context The clinical utility and implications of continuous glucose monitoring (CGM) in cystic fibrosis (CF) are unclear. Objective We examined the correlation between CGM measures and clinical outcomes in adults with CF, investigated the relationship between hemoglobin A1c (HbA1c) and CGM-derived average glucose (AG), and explored CGM measures that distinguish cystic fibrosis–related diabetes (CFRD) from normal and abnormal glucose tolerance. Methods This prospective observational study included 77 adults with CF who had CGM and HbA1c measured at 2 to 3 time points 3 months apart. Results Thirty-one of the 77 participants met American Diabetes Association–recommended diagnostic criteria for CFRD by oral glucose tolerance testing and/or HbA1c. In all participants, CGM measures of hyperglycemia and glycemic variability correlated with nutritional status and pulmonary function. HbA1c was correlated with AG (R2 = 0.71, P < 0.001), with no significant difference between this regression line and that previously established in type 1 and type 2 diabetes and healthy volunteers. Cutoffs of 17.5% time > 140 mg/dL and 3.4% time > 180 mg/dL had sensitivities of 87% and 90%, respectively, and specificities of 95%, for identifying CFRD. Area under the curve and percent of participants correctly classified with CFRD were higher for AG, SD, % time > 140, > 180, and > 250 mg/dL than for HbA1c. Conclusion CGM measures of hyperglycemia and glycemic variability are superior to HbA1c in distinguishing those with and without CFRD. CGM-derived AG is strongly correlated with HbA1c in adults with CF, with a similar relationship to other diabetes populations. Future studies are needed to investigate CGM as a diagnostic and screening tool for CFRD.

Asthma is among the most common medical conditions affecting children and young people, with adolescence a recognised period of increased risk, overrepresented in analyses examining recent increasing asthma mortality rates. Asthma may change significantly during this period and management also occurs in the context of patients seeking increased autonomy and self-governance whilst navigating increasing academic and social demands. A number of disease factors can destabilise asthma during adolescence including: increased rates of anaphylaxis, anxiety, depression, obesity, and, in females, an emerging resistance to corticosteroids and the pro-inflammatory effects of oestrogen. Patient factors such as smoking, vaping, poor symptom recognition, treatment non-adherence and variable engagement with health services contribute to difficult to treat asthma. Significant deficiencies in the current approach to transition have been identified by a recent EAACI task force, and subsequent asthma-specific recommendations, published in 2020 provide an important framework moving forward. As with other chronic conditions, effective transition programmes plan ahead, engage with adolescents and their families to identify the patients’ management priorities and the current challenges they are experiencing with treatment. Transition needs may vary significantly across asthma patients and for more complex asthma may include dedicated transition clinics involving multidisciplinary care requiring input including, amongst others, allergy and immunology, psychological medicine, respiratory physicians and scientists and nurse specialists. Across different global regions, barriers to treatment may vary but need to be elicited and an individualised approach taken to optimising asthma care which is sustainable within the local adult healthcare system.

As people with cystic fibrosis (CF) live longer and healthier lives, increasing numbers are considering the full range of reproductive options for their futures, including parenthood, pregnancy, or pregnancy prevention. As the face of CF changes, the CF care model must adapt to meet the reproductive health needs of both parents and nonparents with CF. This article summarizes the reproductive goals and family-building concerns faced by people with CF, including fertility, pregnancy, and alternative paths to parenthood, the impact of parenthood on mental and physical health, and important future research.

Background Cystic fibrosis related diabetes (CFRD) is associated with pulmonary decline and compromised nutritional status. Emerging data suggest that CFTR dysfunction may play a direct role in the pathogenesis of CFRD; however, studies investigating the effect of CFTR modulators on glycemic outcomes in patients with cystic fibrosis (CF) have shown mixed results. The impact of elexacaftor-tezacaftor-ivacaftor (ETI) on glycemic control is currently unknown. Our objective was to investigate the effect of ETI initiation on glycemia in adults with CF using continuous glucose monitoring (CGM). Methods In this prospective observational study, 34 adults with CF and at least one F508del CFTR mutation wore CGM sensors for 14 days prior to starting ETI and again 3-12 months after ETI initiation. Hypoglycemia symptoms were queried at each visit, and most recent anthropometric measures and spirometry data were obtained by chart review. Results Twenty-three participants completed the study. Compared to baseline, average glucose (AG), standard deviation (SD), % time >200 mg/dL, and peak sensor glucose decreased with ETI treatment, and % time in target range 70-180 mg/dL increased. Improvements in glycemic parameters were most notable in individuals with CFRD. There was no significant change in CGM-measured or self-reported hypoglycemia before and after ETI initiation. Conclusion Initiation of ETI in adults with CF was associated with improvement CGM-derived measures of hyperglycemia and glycemic variability with no effect on hypoglycemia. Further studies are needed to investigate underlying etiology of these changes and the long-term impact of ETI on glycemic control in patients with CF.

Young adults with chronic and complex diseases face systemic barriers, care fragmentation, and increased vulnerabilities. Novel coronavirus pandemic has proven to further complicate care coordination for young adult patients with medical and psychosocial complexities. The BRIDGES Young Adult Program at Boston Children's Hospital has 6 years of experience advocating for and empowering young adults with chronic medical conditions, and their families, through outpatient consults aimed to assist with subspecialty guidance and defragmentation of care during the time of transition from pediatric to adult care. Recently, the BRIDGES consult team developed a pandemic-responsive approach to facilitate individual emergency planning and empowerment of self-management for these high-risk patients. Through the use of a virtual platform, consults were conducted with a multidisciplinary team to support patients and families with system navigation, advance care planning, emergency preparedness, chronic care management, and coping during this time of crisis. BRIDGES aimed to equip patients and families with knowledge and resources, within a rapidly changing environment, to allow for optimal self-care and self-advocacy.

Objective Adolescent and young adult (AYA) women with pediatric-onset chronic diseases, such as cystic fibrosis (CF), face disease-specific sexual and reproductive health (SRH) concerns. Using concept mapping (CM), this study aimed to identify the SRH topics and outcomes valued by AYA women with CF and their parents. Methods Women with CF who were 13 to 30years of age and parents of 13- to 30-year-old daughters with CF participated in an online CM study. Participants individually brainstormed, rated, and sorted SRH topics important for AYA women with CF. Using multidimensional scaling, hierarchical cluster analyses, and t tests to assess rating differences, multidisciplinary stakeholders interpreted results during in-person meetings. Results Twenty-four participants (13 AYAs and 11 parents) generated 109 statements around SRH in CF; 88% completed rating and sorting. Sixteen stakeholders named 6 main clusters of concepts: fertility and pregnancy, deciding to have children, birth control, navigating life, sex, and gynecologic concerns. Participants rated birth control as highest in importance for adolescent women (mean = 3.9 ± 0.1 on a 5-point scale) and fertility and pregnancy as highest for young adult women (mean = 4.2 ± 0.04). Parents provided higher importance ratings for all clusters than patient participants. Stakeholders identified patient-centered outcomes for each cluster and focused on how to improve SRH knowledge, decision making, and patient-provider communication in the subspecialty setting. Conclusions Eliciting patient-centered outcomes using CM can inform improvements in the care of AYAs with pediatric-onset chronic diseases. The SRH topics and patient-centered outcomes identified in this study should inform enhancements to comprehensive clinical care delivery for these populations.

Context Cystic fibrosis (CF) transmembrane conductance (CFTR) dysfunction may play a role in CF-related bone disease (CFBD). Ivacaftor is a CFTR potentiator effective in improving pulmonary and nutritional outcomes in patients with the G551D-CFTR mutation. The effects of ivacaftor on bone health are unknown. Objective To determine the impact of ivacaftor on bone density and microarchitecture in children and adults with CF. Design Prospective observational multiple cohort study. Setting Outpatient clinical research center within a tertiary academic medical center. Patients or Other Participants Three cohorts of age-, race-, and gender-matched subjects were enrolled: 26 subjects (15 adults and 11 children) with CF and the G551D-CFTR mutation who were planning to start or had started treatment with ivacaftor within 3 months (Ivacaftor cohort), 26 subjects with CF were not treated with ivacaftor (CF Control cohort), and 26 healthy volunteers. Interventions All treatments, including Ivacaftor, were managed by the subjects’ pulmonologists. Main Outcome Measures Bone microarchitecture by high-resolution peripheral quantitative computed tomography (HR-pQCT), areal bone mineral density (aBMD) by dual-energy X-ray absorptiometry (DXA) and bone turnover markers at baseline, 1, and 2 years. Results Cortical volume, area, and porosity at the radius and tibia increased significantly in adults in the Ivacaftor cohort. No significant differences were observed in changes in aBMD, trabecular microarchitecture, or estimated bone strength in adults or in any outcome measures in children. Conclusions Treatment with ivacaftor was associated with increases in cortical microarchitecture in adults with CF. Further studies are needed to understand the implications of these findings.

Background: A large‐scale epidemiological study of 6088 individuals with cystic fibrosis (CF) and 4102 caregivers in nine countries documented elevated symptoms of depression and anxiety, leading to international guidelines for annual screening and follow‐up. To facilitate national implementation, 84 CF programs funded a mental health coordinators (MHC). Implementation was evaluated after 1 year using the consolidated framework for implementation research (CFIR) to identify facilitators and barriers.\ud Methods: A 45‐item internet survey was developed to assess relevant CFIR implementation steps. Surveys were completed in 2016. It assessed five domains tailored to study aims: (a) Intervention characteristics, (b) outer setting, (c) inner setting, (d) characteristics of individuals, and (e) process of implementation.\ud Results: Response rate was 88%, with pediatric and adult programs equally represented. A majority of MHCs were social workers (54.1%) and psychologists (41.9%); 41% had joined the team in the past year. Facilitators across the five domains included universal uptake of screening tools, greater awareness and detection of psychological symptoms, reduced stigma, and positive feedback from patients and families. Barriers included limited staff time, space, and logistics.\ud Discussion: This is the largest systematic effort to integrate mental health screening and treatment into the care of individuals with a serious, chronic illness and their caregivers. MHCs implementing screening, interpretation and follow‐up reported\ud positive results, and significant barriers. This national implementation effort demonstrated that depression and anxiety can be efficiently evaluated and treated in a complex, chronic disease. Future efforts include recommending the addition of screening scores to national CF Registries and examining their effects on health outcomes.

Measures of body fat and lean mass may better predict important clinical outcomes in patients with cystic fibrosis (CF) than body mass index (BMI). Little is known about how diet quality and exercise may impact body composition in these patients. Dual X-ray absorptiometry (DXA) body composition, 24-h dietary recall, and physical activity were assessed in a cross-sectional analysis of 38 adolescents and adults with CF and 19 age-, race-, and gender-matched healthy volunteers. Compared with the healthy volunteers, participants with CF had a lower appendicular lean mass index (ALMI), despite no observed difference in BMI, and their diets consisted of higher glycemic index foods with a greater proportion of calories from fat and a lower proportion of calories from protein. In participants with CF, pulmonary function positively correlated with measures of lean mass, particularly ALMI, and negatively correlated with multiple measures of body fat after controlling for age, gender, and BMI. Higher physical activity levels were associated with greater ALMI and lower body fat. In conclusion, body composition measures, particularly ALMI, may better predict key clinical outcomes in individuals with CF than BMI. Future longitudinal studies analyzing the effect of dietary intake and exercise on body composition and CF-specific clinical outcomes are needed.

As life expectancy for people with cystic fibrosis (CF) has increased dramatically, so has the need for a guided, structured transition from pediatric to adult-focused care. A formalized transition program allows for seamless transfer of patients between providers, helping to ensure continuity of care, and avoid potential declines associated with inconsistent medical care. New CF Center guidelines issued by the CFF strongly recommend that each center establish a transition program for age-appropriate transition to an adult CF clinic. In this article, we explore the remaining barriers to establishing a transition program in a CF Center and offer examples of several successful models. We describe CFF-sponsored and other initiatives that exist to support centers in establishing a transition program and discuss the need for ongoing research in this area.

Background Hemoptysis is a major cause of morbidity and mortality in patients with cystic fibrosis (CF). Antifibrinolytic agents have shown efficacy in a broad range of bleeding disorders and conditions. Objectives The goal of this study was to examine the use of antifibrinolytic agents in managing hemoptysis in CF. We developed a clinical treatment pathway for inpatient and outpatient use, and rates of admission for bleeding prior to and following implementation of the pathway are reported. Methods All adult patients with CF treated with systemic antifibrinolytic agents over a 54-month period according to the treatment pathway were analyzed. Data collected included demographic characteristics, baseline CF-related characteristics, and bleeding and treatment parameters. Effectiveness of the pathway was evaluated via comparison of annualized hemoptysis admission rates prior to and following pathway enrollment. Results Seventy-two distinct episodes of hemoptysis treated with antifibrinolytic agents were analyzed in a total of 21 adult patients with CF. Two-thirds of episodes treated involved moderate or massive hemoptysis. Bleeding ceased following a median of 2 days. Outpatient treatment was associated with a 50% reduction in the annualized hemoptysis admission rate following pathway enrollment (2.44 vs 1.23 admissions per year; P = .0024) that was independent of other changes in management. Antifibrinolytic therapy was well tolerated. One central catheter-associated upper extremity DVT was observed in a patient with previous thrombosis in the same vessel. Conclusions A pathway using systemic antifibrinolytic therapy to treat hemoptysis in patients with CF was associated with a reduction in hospital admissions. No serious adverse events were observed. Additional studies are needed to further define the benefits of systemic antifibrinolytic use in patients with CF.

Young adults with cystic fibrosis have compromised plate-like trabecular microstructure, altered axial alignment of trabeculae, and reduced connectivity between trabeculae that may contribute to the reduced bone strength and increased fracture risk observed in this patient population. The risk of fracture is increased in patients with cystic fibrosis (CF). Individual trabecular segmentation (ITS)-based morphological analysis of high-resolution peripheral quantitative computed tomography (HR-pQCT) images segments trabecular bone into individual plates and rods of different alignment and connectivity, which are important determinants of trabecular bone strength. We sought to determine whether alterations in ITS variables are present in patients with CF and may help explain their increased fracture risk. Thirty patients with CF ages 18–40 years underwent DXA scans of the hip and spine and HR-pQCT scans of the radius and tibia with further assessment of trabecular microstructure by ITS. These CF patients were compared with 60 healthy controls matched for age (±2 years), race, and gender. Plate volume fraction, thickness, and density as well as plate-plate and plate-rod connectivity were reduced, and axial alignment of trabeculae was lower in subjects with CF at both the radius and the tibia (p

Background: Patients with cystic fibrosis (CF) are at increased risk for sensorineural hearing loss (SNHL) due, at least in part, to the ototoxic side effects of routine CF therapies. However, the prevalence of SNHL and additional factors contributing to the development of SNHL are unknown. Purpose: To identify risk factors associated with the development of SNHL in a large cohort of CF patients who had been referred for audiometric testing. Research Design: A retrospective study of audiometric results and medication information in a cohort of patients with CF. Study Sample: Records of 178 CF patients seen at Boston Children’s Hospital for audiometric testing from 2007 to 2010 were reviewed. Mean age of patients was 18 yr (standard deviation = 10 yr), and 98 (55%) of the patients were female. Data Collection and Analysis: Audiometric results, medications, and hospitalizations were recorded. Multivariable logistic regression was used to evaluate the association between SNHL and the number of hospitalizations and chronic antibiotic use in the year prior to the patients’ audiometry. Results: In this sample, 37/178 (21%) patients had SNHL. Twenty-nine (78%) of the 37 patients had bilateral SNHL and 8 (22%) had unilateral SNHL. Across all age groups, the majority of patients had a bilateral hearing loss (HL). A multivariable model showed that older age and more frequent hospitalizations were associated with SNHL. The number of courses of chronic antibiotics in the year prior to audiometric testing was not correlated with rate of HL. Conclusions: This study suggests that age and frequency of hospitalizations are key predictors of HL development. Increased awareness and regular screening for SNHL should be included in the routine care of CF patients, particularly those at the highest risk.

While the Fontan procedure has improved life expectancy, patients with single ventricle physiology have impaired exercise capacity due to limited increase in pulmonary blood flow during activity. Enhancing the “thoracic pump” using inspiratory muscle training (IMT) may ameliorate this impairment. Adult nonsmokers with Fontan physiology were recruited through Boston Children's Hospital's outpatient clinic. Participants underwent cardiopulmonary exercise testing and pulmonary function testing, followed by 12 weeks of IMT and then repeat testing. The primary endpoint was change in % predicted peak oxygen consumption (VO2). Secondary endpoints were changes in other exercise metrics. Eleven patients (6 male) were enrolled. Median ages at time of enrollment and Fontan completion were 28.8 years (25.7, 45.5) and 7.8 years (3.9, 16.5), respectively. Average baseline maximal inspiratory pressure (MIP) was normal; only 2 patients had MIP

Preparing a young adult for the eventual transfer from pediatric to adult-centered medical care is a complex process that can be successfully accomplished with appropriate planning. The process can be aided with the development of a transition care consult service. However, the successful transfer of a patient is most often achieved by developing a relationship between pediatric and adult providers while improving communication between these providers during this process. It is also incumbent on providers to prepare patients for the transition process and assist in connecting them to adult caregivers. Ultimately, feedback should be obtained from the patient and providers to improve the experience for future individuals undergoing transition and transfer.

Improvements in clinical care have led to increased life expectancy in patients with cystic fibrosis (CF) over the past several decades. Whether these improvements have had significant effects on bone health in patients with CF is unclear.This is a cross-sectional study comparing clinical characteristics and bone mineral density (BMD) measured by dual energy X-ray absorptiometry (DXA) in adults with CF evaluated in 1995-1999 to age-, race-, and gender-matched patients with CF evaluated in 2011-2013 at the same center on calibrated DXA machines.The cohorts were similar in terms of age, BMI, pancreatic insufficiency, presence of F508del mutation, and reproductive history. In the most recent cohort, pulmonary function was superior, and fewer patients had vitamin D deficiency or secondary hyperparathyroidism. Areal BMD measures of the PA spine, lateral spine, and distal radius were similarly low in the two cohorts.Although pulmonary function and vitamin D status were better in patients in the present-day cohort, areal BMD of the spine was reduced in a significant number of patients and was no different in patients with CF today than in the late 1990s. Further attention to optimizing bone health may be necessary to prevent CF-related bone disease.

Context: Young adults with cystic fibrosis (CF) are at risk for low bone density and fractures, but the underlying alterations in bone microarchitecture that may contribute to their increased fracture risk are currently unknown. Objective: The main goal of this study was to use high-resolution peripheral quantitative computed tomography (HR-pQCT) to characterize the bone microarchitecture, volumetric bone mineral density (vBMD), and estimated strength of the radius and tibia in young adults with CF compared with healthy volunteers. Design and Setting: This was a cross-sectional study at an outpatient clinical research center within a tertiary academic medical center. Participants: Thirty young adults with CF, 18 to 40 years of age, were evaluated and compared with 60 healthy volunteers matched by age (±2 years), gender, and race. Main Outcome Measures: The primary outcomes were HR-pQCT–derived cortical and trabecular vBMD, bone microarchitecture, and estimates of bone strength. Results: At the radius and tibia, young adults with CF had smaller bone cross-sectional area and lower vBMD. Cortical and trabecular microarchitecture were compromised at both sites, most notably involving the trabecular bone of the tibia. These differences translated into lower estimated bone strength both at the radius and tibia. After accounting for body mass index differences, young adults with CF had lower bone area and estimated bone strength at the radius and had compromised trabecular microarchitecture and lower total and trabecular vBMD and estimated bone strength at the tibia. Alterations in trabecular bone density and microarchitecture and estimated strength measures of the tibia were also greater than expected based on dual-energy x-ray absorptiometry-derived areal BMD differences. Conclusions: Young adults with CF have compromised bone microarchitecture and lower estimated bone strength at both the radius and tibia, even after accounting for their smaller body size. These skeletal deficits likely explain the higher fracture risk observed in young adults with CF.

Background Burkholderia dolosa can result in chronic airway infection and rapid decline in lung function in patients with cystic fibrosis (CF). Amiloride has antibacterial properties that may be synergistic with aminoglycosides against other species belonging to the Burkholderia cepacia complex (Bcc). We attempted to eradicate B. dolosa using a combination of nebulized tobramycin and nebulized amiloride in infected CF patients. Methods A 6-month, open-label trial of continuous inhaled amiloride, delivered via nebulization four times daily, and continuous inhaled tobramycin (TIS or TOBI®) nebulized twice daily, was offered to all CF patients at our institution who are chronically infected with B. dolosa . Results Twenty two of 27 patients with B. dolosa were eligible and twelve elected to participate. Eradication of B. dolosa was not noted in any study subject. While patients tolerated treatment with no adverse effects, there was also no apparent impact on other secondary outcome measures. Conclusions Concurrent, continuous inhalation of amiloride and tobramycin for 6 months was not effective for the eradication of chronic B. dolosa airway infection in CF patients.

Objectives Nasal potential difference (NPD) measurement is part of the diagnostic criteria for cystic fibrosis (CF) and now used routinely as an endpoint in clinical trials of correcting the basic defect in CF. Intestinal current measurement (ICM), measured ex vivo on a rectal biopsy, has been used to study cystic fibrosis transmembrane conductance regulator (CFTR) function but has not been compared to NPD in the same subject in adults and children. The aim of the study is to evaluate the potential usefulness of ICM as a marker of CFTR function for treatment studies compared NPD in patients with CF and in healthy control subjects. Methods ICM and NPD were performed on healthy controls and patients with CF. The healthy adults were individuals undergoing routine screening colonoscopy at the Beth Israel Deaconess Medical Center. The healthy children were undergoing colonoscopy for suspicion of inflammation in Hadassah Hebrew University Medical Center. The CF adults were recruited from Boston Children's Hospital CF Center and CF Center Worcester Mass, the children with CF from Hadassah CF Center. Results ICM measurements in healthy control subjects (n = 16) demonstrated a mean (±SE) carbachol response of 16.0 (2.2) μA/cm, histamine response of 13.2 (2.1) μA/cm and a forskolin response of 6.3 (2.0) μA/cm. Basal NPD of -15.9 (1.9) and response to Cl free + isoproterenol of -13.8 (2.0). These responses were inverted in CF subjects (n = 12) for ICM parameters with carbachol response of -3.0 (0.5) μA/cm, histamine -1.0 (0.8) μA/cm and a forskolin response of 0.5 (0.3) and also for NPD parameters; basal NPD of -42.2 (4.3) and response to Cl free + isoproterenol of 4.3 (0.7). Pearson correlation test showed the comparability of ICM and NPD in assessing CFTR function. Conclusions ICM is equivalent to NPD in the ability to distinguish patients with CF from controls and could be used as surrogate markers of CFTR activity in treatment protocols.

Objectives: A defect in bicarbonate secretion contributes to the pathophysiology of gastrointestinal complications in patients with cystic fibrosis (CF). We measured gastrointestinal pH, clinical outcomes, and intestinal transit profiles in patients with the G551D mutation before and after treatment with ivacaftor, a CF transmembrane regulator channel (CFTR) potentiator. Methods: Observational studies of ivacaftor effectiveness were conducted in the United States and Canada. A subset of subjects ingested a wireless motility capsule (n=10) that measures in vivo pH, both before therapy with ivacaftor and 1 month after treatment; values obtained were compared for mean pH and area under the pH curve, and regional intestinal motility. We also queried subjects about abdominal pain and recorded body weight before and after treatment. Results: One month after administering ivacaftor, a significant increase in mean pH was observed after gastric emptying (P30 min); mean weight gain was 1.1 kg (P=0.08). No difference in abdominal pain or regional transit times was seen. Conclusions: CFTR modulation improves the proximal small intestinal pH profile in patients with the G551D CFTR mutation and we observed clinically relevant, contemporaneous weight gain, although it did not reach statistical significance. These data provide in vivo evidence that CFTR is an important regulator of bicarbonate secretion, which may be a translational link between CFTR function and clinical improvement.

We sought to examine the employment experiences in a population of adolescents and young adults with cystic fibrosis (CF).We administered a cross-sectional survey to 68 individuals with CF, ages 16-25 years, assessing current employment experiences and perceptions of the impact of CF on these experiences.Forty-six percent of respondents reported working 20 h per week. Sixty-seven percent reported disclosing their diagnosis to their employer. Only one respondent reported receiving formal job guidance in CF clinic, and only 16% reported that a clinician had discussed job-related issues with them. Only 21% reported that they completed CF therapies at work. Older respondents (ages 22-25 years) and those with a lower lung function were more likely to agree that 'balancing employment and CF care is stressful.'The majority of adolescents and young adults with CF report disclosing their diagnosis at work. Most do not feel that working interferes with routine CF therapies. Very few have received any formal career guidance. Age and lung disease severity are associated with increased concerns about balancing CF care and employment.

Cystic fibrosis (CF) is a recessive genetic disease characterized by dehydration of the airway surface liquid and impaired mucociliary clearance. As a result, individuals with the disease have difficulty clearing pathogens from the lung and experience chronic pulmonary infections and inflammation. There may be intermittent pulmonary exacerbations or acute worsening of infection and obstruction, which require more intensive therapies. Hemoptysis and pneumothorax are complications commonly reported in patients with cystic fibrosis.This document presents the CF Foundation's Pulmonary Therapies Committee recommendations for the treatment of hemoptysis and pneumothorax.The committee recognized that insufficient data exist to develop evidence-based recommendations and so used the Delphi technique to formalize an expert panel's consensus process and develop explicit care recommendations.The expert panel completed the survey twice, allowing refinement of recommendations. Numeric responses to the questions were summarized and applied to a priori definitions to determine levels of consensus. Recommendations were then developed to practical treatment questions based upon the median scores and the degree of consensus.These recommendations for the management of the patient with CF with hemoptysis and pneumothorax are designed for general use in most individuals but should be adapted to meet specific needs as determined by the individuals, their families, and their health care providers. It is hoped that the guidelines provided in this manuscript will facilitate the appropriate application of these treatments to improve and extend the lives of all individuals with cystic fibrosis.

Rationale Monitoring clinical disease status in cystic fibrosis frequently requires invasive collection of clinical samples. Due to its noninvasive collection process and direct anatomic relationship with the lower airway, saliva shows great potential as a biological fluid for cystic fibrosis monitoring. Objectives To measure the levels of multiple protein markers in human saliva supernatants and investigate the possibility of utilizing them to provide a more quantitative measure of disease state for use in research and monitoring of patients with cystic fibrosis clinically. Methods Whole saliva samples were collected and processed from cystic fibrosis patients at two distinct time points (2010 and 2013) and measured by two separate platforms. In this cross sectional study, a convenience sample of 71 participants were recruited with samples measured by multiplexed fluorescence microarray (fiber microarray) and another 117 participant samples were measured by an automated, point-of-care, analyzer (SDReader) using a microsphere-based array via fluorescence sandwich immunoassay. For comparison, saliva from 56 and 50 healthy subjects were collected, respectively. The levels of six target proteins were quantified. Various demographic and clinical data, including spirometry, medical history, and clinicians’ assessments were also collected from patients with cystic fibrosis on the day of saliva collection. Measurements and Main Results Similar trends were observed with both platforms and compared with healthy subjects, cystic fibrosis patients had significantly elevated levels of VEGF, IP-10, IL-8, and EGF as well as lower levels of MMP-9 (P ≤ 0.005) using fiber microarray and significantly elevated levels of IP-10, IL-8 with lower levels of MMP-9 and IL-1β (P ≤ 0.02) using the SDReader. The levels of the six proteins correlated with each other significantly, and in some cases, biomarker levels could be used to differentiate between subgroups of patients with different clinical presentations. For example, IP-10 levels significantly correlated with FEV1 and disease severity (as evaluated by clinicians) with both platforms (P < 0.05). Conclusions Significant variations of the levels of six proteins in saliva supernatants, and the correlations of these levels with clinical assessments, demonstrated the potential of saliva for cystic fibrosis research and monitoring.

During the last decade, saliva has emerged as a potentially ideal diagnostic biofluid for noninvasive testing. In this paper, we present an automated, integrated platform useable by minimally trained personnel in the field for the diagnosis of respiratory diseases using human saliva as a sample specimen. In this platform, a saliva sample is loaded onto a disposable microfluidic chip containing all the necessary reagents and components required for saliva analysis. The chip is then inserted into the automated analyzer, the SDReader, where multiple potential protein biomarkers for respiratory diseases are measured simultaneously using a microsphere-based array via fluorescence sandwich immunoassays. The results are read optically, and the images are analyzed by a custom-designed algorithm. The fully automated assay requires as little as 10 μL of saliva sample, and the results are reported in 70 min. The performance of the platform was characterized by testing protein standard solutions, and the results were comparable to those from the 3.5-h lab bench assay that we have previously reported. The device was also deployed in two clinical environments where 273 human saliva samples collected from different subjects were successfully tested, demonstrating the device’s potential to assist clinicians with the diagnosis of respiratory diseases by providing timely protein biomarker profiling information. This platform, which combines non-invasive sample collection and fully automated analysis, can also be utilized in point-of-care diagnostics.

To determine the prevalence of sensorineural hearing loss (SNHL) in cystic fibrosis (CF) patients and its relationship to antibiotic use.Case series with chart review.Tertiary care pediatric hospital.We reviewed the medical records of CF patients seen in our children's hospital between March 1994 and December 2007. Data collected included patient demographics, audiograms, tympanograms, genotype, and use of potentially ototoxic antibiotics.Seven of 50 (14%) patients had SNHL. Three percent of patients who receivedor=10 courses of intravenous aminoglycosides had SNHL versus 43 percent of those who received10 courses (P0.01). No patients who received five or fewer courses of nasal irrigation with aminoglycosides had SNHL versus 23 percent of those who received more than five courses (P0.05). Nine percent of patients who received five or fewer courses of macrolides had SNHL versus 60 percent of those who received more than five courses (P=0.079).CF patients receiving aminoglycosides are at high risk for developing SNHL.