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Better health and longer survival for many people with cystic fibrosis (PwCF) compels the continued evolution of the CF care model. Designed to deliver specialized care for a complex chronic condition, the model is organized around interdisciplinary healthcare teams at dedicated care centers. Introduction of CFTR modulators and the COVID-19 pandemic have catalyzed the model's evolution. Many PwCF on modulator therapies are experiencing better health and considering changes in their daily care routines. Some of the growing number of adults with CF are experiencing age-associated co-morbidities, requiring coordination with new specialists. The pandemic accelerated the use of telehealth, revealing tradeoffs from new configurations of care delivery. Herein we review the implications of these recent shifts and offer recommendations to improve the quality of care coordinated across the interdisciplinary teams and an expanding field of subspecialists, while supporting the ability of the patient to take on greater responsibility in disease management.

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 Understanding how health outcomes differ for patients with advanced cystic fibrosis (CF) lung disease living in the United States compared with Canada has health policy implications. Research Question What are rates of lung transplant (LTx) and rates of death without LTx in the United States and Canada among individuals with FEV1 Study Design and Methods This was a retrospective population-based cohort study, 2005 to 2016, using the US CF Foundation, United Network for Organ Sharing, and Canadian CF registries. Individuals with CF and at least two FEV1 measurements Results There were 5,899 patients (53% male) and 905 patients (54% male) with CF with FEV1 Interpretation There are lower rates of LTx and an increased risk of death without LTx for US patients with CF with FEV1

Previous literature in cystic fibrosis (CF) has shown a 10-year survival gap between Canada and the United States (US). We hypothesized that differential access to and survival after lung transplantation may contribute to the observed gap. The objectives of this study were to compare CF transplant outcomes between Canada and the US and estimate the potential contribution of transplantation to the survival gap.Data from the Canadian CF Registry and the US Cystic Fibrosis Foundation Patient Registry supplemented with data from United Network for Organ Sharing were used. The probability of surviving after transplantation between 2005 and 2016 was calculated using the Kaplan‒Meier method. Survival by insurance status at the time of transplantation and transplant center volume in the US were compared with those in Canada using Cox proportional hazard models. Simulations were used to estimate the contribution of transplantation to the survival gap.Between 2005 and 2016, there were 2,653 patients in the US and 470 in Canada who underwent lung transplantation for CF. The 1-, 3-, and 5-year survival rates were 88.3%, 71.8%, and 60.3%, respectively, in the US compared with 90.5%, 79.9%, and 69.7%, respectively, in Canada. Patients in the US were also more likely to die on the waitlist (p0.01) than patients in Canada. If the proportion of who underwent transplantation and post-transplant survival in the US were to increase to those observed in Canada, we estimate that the survival gap would decrease from 10.8 years to 7.5 years.Differences in waitlist mortality and post-transplant survival can explain up to a third of the survival gap observed between the US and Canada.

Introduction In this long-term, postapproval, observational study, data from the US Cystic Fibrosis Foundation Patient Registry and the UK Cystic Fibrosis Registry were used to evaluate the impact of ivacaftor treatment on cystic fibrosis (CF) by comparing outcomes in ivacaftor-treated patients with those in matched untreated comparator patients. Registry data from up to 5 years of ivacaftor availability in the US and up to 4 years of availability in the UK were evaluated. Methods Starting in the first year of ivacaftor availability, ivacaftor-treated patients in each registry were matched 1:5 to comparator patients who never received ivacaftor. Clinical endpoints were evaluated in annual cross-sectional safety analyses. The key endpoints were death, organ transplants, pulmonary exacerbation, and hospitalization. Relative risks and 95% CIs were calculated to compare the ivacaftor and comparator cohorts in each registry. Results Here, we report the complete and final results of the annual cross-sectional safety analyses across the duration of the study, with up to 5 years of follow-up. Data show a pattern of lower risk of death, transplant, pulmonary exacerbation, and hospitalization among ivacaftor-treated patients in both registries. Conclusions Ivacaftor-treated patients had consistently favorable clinical outcomes relative to untreated comparators, and no new safety concerns were identified. While general limitations of observational research apply, these findings support disease modification by CF transmembrane conductance regulator (CFTR) modulator therapy with ivacaftor. Future research of novel CFTR modulators will need to explore alternative methods for comparator selection for evaluation of clinical data given the evolving landscape of CF treatment., Plain Language Summary We performed a study to better understand the long-term impact of treatment with a drug called ivacaftor for patients with cystic fibrosis (CF). Our study used data from CF patient registries in the United Kingdom and the United States. These registries collect information about patients with CF, their health, and the treatments they receive. Using data from these registries, we compared patients treated with ivacaftor with a similar group of patients (similar age, sex, and disease severity) who did not receive ivacaftor. We looked at the clinical outcomes of each group every year for up to 5 years. In the final analysis from our study, we found no new safety concerns associated with ivacaftor treatment. Additionally, we found that patients treated with ivacaftor tended to have lower risks of death, organ transplant, pulmonary exacerbations, and hospitalizations. Overall, these results demonstrate the favorable impact of ivacaftor treatment on long-term outcomes of patients with CF.

BACKGROUND: Although guidelines for inhaled therapies for individuals with cystic fibrosis (CF) are available, recommendations for compressors/nebulizers to optimize care are lacking. The CF Foundation (CFF) convened a multidisciplinary task force to assess the use, durability, accessibility, and cost burden of compressors/nebulizers. METHODS: Online surveys were developed and distributed to 287 CFF programs and adults with CF and parents of children with CF (adults with CF/parents). RESULTS: Health care providers from 38 states completed the survey (59% response rate). Respiratory therapists were mostly responsible to coordinate ordering nebulizers and compressors. Durable medical equipment companies were the most common source of acquisition of compressors (71.8%) and nebulizers (45.9%). A majority of health care providers did not feel the compressors were durable (51.1%) or that they could get enough nebulizers to their patients (69.2%). Barriers to procure compressors were reported. The survey was completed by 734 adults with CF/parents from 48 states. Most adults with CF/parents rated their compressor as durable (65.8%); however, 85.5% of respondents reported some user-experience problem(s). “Hoses popping off” and “increased nebulization time” were most commonly reported. Almost 20% of respondents did not have access to a compressor at some point in the previous year. Most adults with CF/parents did not change compressor filters per manufacturer’s recommendation (40% never). Adults with CF/parents reported performing a median of 4 inhaled treatments per day. Median use of nebulizers was 6 months. Most adults with CF/parents thought they had enough nebulizers (53.7%). Individuals with CF doing more inhaled treatments reported more compressor malfunctions. The median out-of-pocket expense was $75–99 and $50–74 for compressors and nebulizers, respectively. CONCLUSIONS: Although the perceptions of health care providers and adults with CF/parents differed to a certain extent, the surveys uncovered several significant issues that may compromise quality of care. Improvement in access to devices and education are needed.

Background In this study, we report clinical outcomes in COVID-19 infection in a large cohort of people with cystic fibrosis (pwCF) and compare these outcomes to a propensity score matched cohort of people without CF. Methods Analysis of a multicenter research network TriNETX was performed including patients more than 16 years of age diagnosed with COVID-19. Outcomes in COVID-19 positive pwCF were compared with a propensity-matched cohort of people without CF. Results A total of 507,810 patients with COVID-19 were included (422 patients, 0.08% with CF; 507,388 patients, 99.92% without CF. Mean age at COVID-19 diagnosis in CF cohort was 46.6 ± 19.3 years, with female predominance (n = 225, 53.32%). Majority of the participants were Caucasian (n = 309, 73.22%). In the crude, unmatched analysis, mortality, hospitalization, critical care need, mechanical ventilation, acute kidney injury and composite (combination of intubation and mortality) outcome at 30 days was higher in the pwCF. Following robust propensity matching, pwCF had higher hospitalization rate (RR 1.56, 95% CI 1.20–2.04), critical care need (RR 1.78, 95% CI 1.13–2.79), and acute renal injury (RR 1.60, 95% CI 1.07–2.39) as compared to patients without CF. Conclusion People with CF are at risk of poor outcomes with COVID-19.5.2% of these patients died within one month of COVID-19 diagnosis, and more than one in 10 patients required critical care. Therefore, the relatively young median age of cystic fibrosis patients, and lower prevalence of obesity do not protect these patients from severe disease contrary to prior reports.

RationaleA previous analysis found significantly higher lung function in the US paediatric cystic fibrosis (CF) population compared with the UK with this difference apparently decreasing in adolescence and adulthood. However, the cross-sectional nature of the study makes it hard to interpret these results.ObjectivesTo compare longitudinal trajectories of lung function in children with CF between the USA and UK and to explore reasons for any differences.MethodsWe used mixed effects regression analysis to model lung function trajectories in the study populations. Using descriptive statistics, we compared early growth and nutrition (height, weight, body mass index), infections (Pseudomonas aeruginosa, Staphylococcus aureus) and treatments (rhDnase, hypertonic saline, inhaled antibiotics).ResultsWe included 9463 children from the USA and 3055 children from the UK with homozygous F508del genotype. Lung function was higher in the USA than in the UK when first measured at age six and remained higher throughout childhood. We did not find important differences in early growth and nutrition, or P.aeruginosa infection. Prescription of rhDNase and hypertonic saline was more common in the USA. Inhaled antibiotics were prescribed at similar levels in both countries, but Tobramycin was prescribed more in the USA and colistin in the UK. S. aureus infection was more common in the USA than the UK.ConclusionsChildren with CF and homozygous F508del genotype in the USA had better lung function than UK children. These differences do not appear to be explained by early growth or nutrition, but differences in the use of early treatments need further investigation.

The findings of this body of work are presented in the eight articles included in this supplement. The impact and perspectives of adult and pediatric care teams and patient/families are covered with special attention to mental health care, the financial and personnel impacts within care programs, the experiences of vulnerable and underrepresented patient populations, and implementation of remoting monitoring. Commentaries from colleagues provide a broader perspective, offering reflections on the findings and their implications regarding the future CF care model.

The approval of aztreonam lysine for inhalation solution (AZLI) raised concerns that additional antibiotic exposure would potentially affect the susceptibility profiles of Pseudomonas aeruginosa isolates from cystic fibrosis (CF) patients. This 5-year, prospective, observational study tracked susceptibility changes and clinical outcomes in CF patients in the United States with chronic P. aeruginosa infection., The approval of aztreonam lysine for inhalation solution (AZLI) raised concerns that additional antibiotic exposure would potentially affect the susceptibility profiles of Pseudomonas aeruginosa isolates from cystic fibrosis (CF) patients. This 5-year, prospective, observational study tracked susceptibility changes and clinical outcomes in CF patients in the United States with chronic P. aeruginosa infection. Sputum cultures were collected annually (2011 to 2016). The primary study endpoint was the proportion of subjects whose least susceptible P. aeruginosa isolate had an aztreonam MIC that was >8 μg/ml (parenteral breakpoint) and increased ≥4-fold compared with the least susceptible isolate from the previous year. Annualized data for pulmonary exacerbations, hospitalizations, and percent of predicted forced expiratory volume in 1 s (FEV1% predicted) were obtained from the CF Foundation Patient Registry and compared between subjects meeting and those not meeting the primary endpoint. A total of 510 subjects were enrolled; 334 (65%) completed the study. A consistent proportion of evaluable subjects (13 to 22%) met the primary endpoint each year, and AZLI use during the previous 12 months was not associated with meeting the primary endpoint. While the annual declines in lung function were comparable for subjects meeting and those not meeting the primary endpoint, more pulmonary exacerbations and hospitalizations were experienced by those who met it. The aztreonam susceptibility of P. aeruginosa remained consistent during the 5-year study. The relationship between P. aeruginosa isolate susceptibilities and clinical outcomes is complex; reduced susceptibility was not associated with an accelerated decline in lung function but was associated with more exacerbations and hospitalizations, likely reflecting increased overall antibiotic exposure. (This study has been registered at ClinicalTrials.gov under identifier NCT01375036.)

DISCLOSURES: No funding contributed to the writing of this commentary. Both authors are employed by the Cystic Fibrosis Foundation. The Cystic Fibrosis Foundation has entered into therapeutic devel...

Highlights • There is a need for adult and pediatric gastroenterologists with expertise in CF. • The DIGEST program was created to meet this need. • This article reports on the development, implementation and results of DIGEST., Individuals with cystic fibrosis (CF) now have an increased life expectancy, due to advances in care provided by a multidisciplinary team. The care model has expanded over time to include multiple subspecialties. The Cystic Fibrosis Foundation conducted a survey of Care Center Directors and identified a need for pediatric and adult gastroenterologists with expertise in the diagnosis and treatment of intestinal, pancreatic and hepatic complications of CF. To address this need, the Developing Innovative GastroEnterology Specialty Training (DIGEST) program was created. The development, implementation, and early results of this training program are reported herein.

Background The Standardized Treatment of Pulmonary Exacerbations (STOP) program has the intent of defining best practices in the treatment of pulmonary exacerbations (PEx) in patients with cystic fibrosis (CF). The objective of this analysis was to describe the clinical presentations of patients admitted for intravenous (IV) antibiotics and enrolled in a prospective observational PEx study as well as to understand physician treatment goals at the start of the intervention. Methods We enrolled adolescents and adults admitted to the hospital for a PEx treated with IV antibiotics. We recorded patient and PEx characteristics at the time of enrollment. We surveyed treating physicians on treatment goals as well as their willingness to enroll patients in various study designs. Additional demographic and clinical data were obtained from the CF Foundation Patient Registry. Results Of 220 patients enrolled, 56% were female, 19% were adolescents, and 71% were infected with P. aeruginosa. The mean (SD) FEV1 at enrollment was 51.1 (21.6)% predicted. Most patients (85%) experienced symptoms for ≥ 7 days before admission, 43% had received IV antibiotics within the previous 6 months, and 48% received oral and/or inhaled antibiotics prior to IV antibiotic initiation. Forty percent had ≥ 10% FEV1 decrease from their best value recorded in the previous 6 months, but for 20% of patients, their enrollment FEV1 was their best FEV1 recorded within the previous 6 months. Physicians reported that their primary treatment objectives were lung function recovery (53%) and improvement of symptoms (47%) of PEx. Most physicians stated they would enroll patients in studies involving 10-day (72%) or 14-day (87%), but not 7-day (29%), treatment regimens. Conclusions Based on the results of this study, prospective studies are feasible and physician willingness for interventional studies of PEx exists. Results of this observational study will help design future PEx trials.

Background Healthcare coproduction engages patients and clinicians to design and execute services, yet little is known about tools that facilitate coproduction. Our objective was to understand uptake, experiences, benefits, and limitations of a dashboard to support patient-clinician partnerships within the cystic fibrosis (CF) community. Methods People living with CF (PwCF) and clinicians co-designed a dashboard that displayed patient-reported and clinical data. Eight CF programmes, including 21 clinicians, and 131 PwCF participated in a pilot study of the dashboard. We conducted descriptive statistics and thematic analyses of surveys (82 PwCF; 21 clinicians); semi-structured interviews (13 PwCF; 8 care teams); and passively-collected usage data. Results Two-thirds of the 82 PwCF used the dashboard during a visit, and 59% used it outside a visit. Among 48 PwCF using the dashboard outside the clinic, 92% viewed their health information and 46% documented concerns or requests. Most of the 21 clinicians used the dashboard to support visit planning (76%); fewer used it during a visit (48%). The dashboard supported discussions of what matters most (69% PwCF; 68% clinicians). Several themes emerged: access to patient outcomes data allows users to learn more deeply; participation in pre-visit planning matters; coproduction is made possible by inviting new ways to partner; and lack of integration with existing information technology (IT) systems is limiting. Conclusions A dashboard was feasible to implement and use. Future iterations should provide patients access to their data, be simple to use, and integrate with IT systems in use by clinicians and PwCF.

Background Ivacaftor is the first in a class of drugs, CFTR modulators, that target the underlying defect in cystic fibrosis (CF). This long-term observational safety study evaluated CF disease progression in patients treated with ivacaftor in a real-world setting for up to 5 years. Methods Data from existing US and UK CF patient registries were used to assess longitudinal patterns in lung function, nutritional status, pulmonary exacerbations and hospitalizations, CF-related diabetes (CFRD), and Pseudomonas aeruginosa in ivacaftor-treated vs untreated comparator cohorts matched by age, sex, and disease severity. Results US analyses included 635 ivacaftor-treated patients and 1874 comparators followed for 5 years from year 1 of market availability (2012–2016). Evaluation of outcome patterns from pretreatment baseline (2011) through year 5 (2016), showed that relative to comparators, ivacaftor-treated patients had better preserved lung function (mean change in percent predicted FEV1, −0.7 percentage points with ivacaftor vs −8.3 percentage points in comparators) and improved nutritional status (mean body mass index change +2.4 kg/m2 with ivacaftor vs +1.6 kg/m2 in comparators). US patients treated with ivacaftor had significantly lower frequencies of exacerbations and hospitalizations in each of the 5 years of follow-up relative to pretreatment baseline and comparators. Favorable trends in CFRD and P. aeruginosa prevalence were also observed. Findings from the smaller UK registry were directionally similar to and consistent with US findings. Conclusions This observational study represents the largest longitudinal analysis of patients treated with ivacaftor in a real-world setting. The findings support disease modification by CFTR modulation with ivacaftor.

Objectives: As the novel coronavirus (SARS-CoV-2) pandemic continues, people with cystic fibrosis (CF) have been identified as being a vulnerable group. It is essential that people with CF, their families and their clinical teams have the most up-to-date information on the impact of SARS-CoV-2 on their health. This study aims to characterise the impact of SARS-CoV-2 infection in people with CF throughout 2020, identify factors that predict clinical progression of COVID-19, and to describe medium-term follow-up of people who have been infected. Methods: The ‘Cystic Fibrosis Registry Global Harmonization Group’ is a worldwide network of CF Registries that each contributed data on people with CF diagnosed with SARS-CoV-2 infection. In this analysis, we will report on cases contributed from 22 countries diagnosed between 1st February and 13th December 2020. We will present demographic, pre-infection clinical characteristics, symptoms, infection management and outcomes. We will use multivariable logistic regression to assess predictors for hospitalisation with respiratory support and intensive care admission as the outcomes of interest representing clinical progression of COVID-19. Descriptive analysis of medium-term follow-up BMI and FEV1% predicted values will also be undertaken. Results: Results pending. Expected cohort size >1,000, including the 181 previously reported in our paper “The global impact of SARS-CoV-2 in 181 people with cystic fibrosis.” Conclusion: It is expected that the findings of this study will have important implications for shielding advice, clinical care and vaccine prioritisation for people with CF.

The Cystic Fibrosis Foundation Patient Registry (CFFPR) is an ongoing patient registry study that collects longitudinal demographic, clinical, and treatment information about persons with cystic fibrosis (CF) in the United States. CF is a life-shortening genetic disorder that occurs in approximately 1 in 3,500 births in the United States. High-quality observational data is important for clinical research, quality improvement, and clinical management.To describe the data collection, patient population, and key limitations of the CFFPR.Inclusion criteria for the CFFPR include diagnosis with CF or a CFTR-associated disorder, care at an accredited care center program, and provision of informed consent. Data from clinic visits and hospitalizations are collected through a secure website. Loss to follow-up and generalizability were examined using several methods. The accuracy of CFFPR data was evaluated with an audit of 2012 CFFPR data compared to the medical record.Since 1986, the CFFPR contains the records of 48,463 individuals with CF. Participation among individuals seen at accredited care centers is high, and loss to follow-up is low. An audit of 2012 CFFPR data suggests that the CFFPR contains 95% of clinic visits and 90% of hospitalizations found in the medical record for these patients, and nearly all of the audited fields were highly accurate.Registries such as the CFFPR are important tools for research, clinical care, and tracking incidence, mortality and population trends.

Objectives Our objective was to quantify the effect of different statistical techniques, inclusion/exclusion criteria, and missing data on the predicted median survival age. Study Design and Setting Using the Canadian cystic fibrosis registry (CCFR), the median age of survival was calculated using both the Cox proportional hazards (PH) and the life-table methods. Through simulations, we examined how the median age of survival would change when: (1) patients were excluded, (2) death dates were inaccurate, (3) patients were lost to follow-up, (4) entire years with no clinic visits were excluded even if the​ patient had a visit in subsequent years, and (5) censoring patients at their date of transplant. Simulations were run assuming 5–35% of data were affected by each scenario. Results Over the period 2009–2013, there were 4,666 individuals in the CCFR with 240 deaths. The observed median age of survival calculated by the Cox PH method was 50.9 [95% confidence interval (CI): 47.4, 54.3] and 50.5 from the life-table method (95% CI: 47.5, 53.5). Censoring patients at their transplant date overestimated the median age of survival by 7.2 years (58.1; 95% CI: 53.3, 64.7). Simulations determined that by missing just 15% of deaths, the median age of survival can be overestimated by 3.5 years (54.4; 95% CI: 54.2, 56.1), and having 25% of patients lost to follow-up can underestimate the median age of survival by 3.3 years (47.6; 95% CI: 46.8, 47.7). Conclusion We present several recommendations to assist national cystic fibrosis registries in calculating and reporting the median age of survival in a standardized fashion. It is imperative to state the statistical method used as well as the proportion lost to follow-up and the treatment of missing data and transplanted patients. Registries must be diligent in their data collection as incomplete data can lead to overestimation and underestimation of survival.

Background Monitoring potential changes in the epidemiology of cystic fibrosis (CF) pathogens furthers our understanding of the potential impact of interventions. Methods We performed a retrospective analysis using data reported to the Cystic Fibrosis Foundation Patient Registry (CFFPR) from 2006 to 2012 to determine the annual percent changes in the prevalence and incidence of selected CF pathogens. Pathogens included Pseudomonas aeruginosa , methicillin-susceptible Staphylococcus aureus (MSSA), methicillin-resistant S aureus (MRSA), Haemophilus influenzae , Burkholderia cepacia complex, Stenotrophomonas maltophilia , and Achromobacter xylosoxidans . Changes in nontuberculous mycobacteria (NTM) prevalence were assessed from 2010 to 2012, when the CFFPR collected NTM species. Results In 2012, the pathogens of highest prevalence and incidence were MSSA and P aeruginosa , followed by MRSA. The prevalence of A xylosoxidans and B cepacia complex were relatively low. From 2006 to 2012, the annual percent change in overall (as well as in most age strata) prevalence and incidence significantly decreased for P aeruginosa and B cepacia complex, but significantly increased for MRSA. From 2010 to 2012, the annual percent change in overall prevalence of NTM and Mycobaterium avium complex increased. Conclusions The epidemiology of CF pathogens continues to change. The causes of these observations are most likely multifactorial and include improvements in clinical care and infection prevention and control. Data from this study will be useful to evaluate the impact of new therapies on CF microbiology.

BackgroundIvacaftor is the first cystic fibrosis transmembrane conductance regulator (CFTR) modulator demonstrating clinical benefit in patients with cystic fibrosis (CF). As ivacaftor is intended for chronic, lifelong use, understanding long-term effects is important for patients and healthcare providers.ObjectiveThis ongoing, observational, postapproval safety study evaluates clinical outcomes and disease progression in ivacaftor-treated patients using data from the US and the UK CF registries following commercial availability.MethodsAnnual analyses compare ivacaftor-treated and untreated matched comparator patients for: risks of death, transplantation, hospitalisation, pulmonary exacerbation; prevalence of CF-related complications and microorganisms and lung function changes in a subset of patients who initiated ivacaftor in the first year of commercial availability. Results from the 2014 analyses (2 and 3 years following commercial availability in the UK and USA, respectively) are presented here.ResultsAnalyses included 1256 ivacaftor-treated and 6200 comparator patients from the USA and 411 ivacaftor-treated and 2069 comparator patients from the UK. No new safety concerns were identified based on the evaluation of clinical outcomes included in the analyses. As part of safety evaluations, ivacaftor-treated US patients were observed to have significantly lower risks of death (0.6% vs 1.6%, p=0.0110), transplantation (0.2% vs 1.1%, p=0.0017), hospitalisation (27.5% vs 43.1%, pConclusionsWhile general limitations of observational research apply, analyses revealed favourable results for clinically important outcomes among ivacaftor-treated patients, adding to the growing body of literature supporting disease modification by CFTR modulation with ivacaftor.EU PAS registration numberEUPAS4270

Background Between 2002 and 2006 France launched a national cystic fibrois (CF) newborn screening program; organized a network of specialized CF care centers; and issued CF diagnostic and treatment standards. To continue to build on this success in 2007 the Cystic Fibrosis Center of Expertise for Rare Diseases (CF CERD) of Nantes-Roscoff in partnership with the French CF Society, the French CF Association (Vaincre la Mucoviscidose), and all CF center leaders from across the country agreed to pursue center-level improvement in medical outcomes for people with CF by adapting the U.S. Cystic Fibrosis Foundation’s (US CFF) national initiative, Accelerating the Rate of Improvement in CF Care. To launch the Program to Improve Results and Expertise in CF (le Programme d’Amélioration des Résultats et de l’Expertise en Mucoviscidose - PHARE-M), French leaders pursued mentorship and guidance from leaders at the US CFF, the Dartmouth Institute (TDI), and clinical care teams at CF centers across the U.S. Methods The following activities enabled the Nantes-Roscoff CF CERD team members and a parent, involved with the French CF Association board and a quality engineer by training, to gain the leadership and quality improvement knowledge and skills necessary to implement the PHARE-M program: 1) regularly attending national meetings, tracking publications, and leveraging existing partnerships; 2) completing two sabbaticals to visit U.S. CF centers and enrolling in academic and professional training courses; and, 3) inviting US CFF and TDI leaders to France to meet key opinion leaders and frontline teams. Conclusions The Nantes-Roscoff CF CERD team successfully adapted the US CFF’s initiative to accelerate improvement in CF care by establishing a partnership with U.S. leaders to communicate and exchange strategies and lessons learned; intentionally studying and adapting the Clinical Microsystems approach to quality improvement; and learning directly from the experience of frontline teams in the U.S. They continue to partner with U.S. leaders and are seeking to collaborate with European colleagues to continue to improve care for individuals with CF and their families across Europe.

A 10-year gap in the median age of survival for patients with cystic fibrosis (CF) was reported between patients living in Canada compared with patients living in the United States.Because both malnutrition and poor lung function are associated with an increased risk of mortality in CF, we investigated the temporal and longitudinal trends in lung function and nutrition between Canada and the United States.This cohort study used Canadian CF Registry and U.S. CF Foundation Patient Registry data from 1990 to 2013. A unified dataset was created to harmonize the variables collected within the two registries for the purpose of comparing outcomes between the two countries.We conducted three analyses: survival differences by birth cohort; population trends for FEVThe reasons for the observed improvements, and catch-up in the United States, are likely multifactorial and include the introduction of high-fat, high-calorie diets; introduction of newborn screening; and/or improved access to care for CF children in the United States.

Introduction In 2012 and 2013, 30 adult and 40 pediatric CF Foundation-accredited programs across the United States recruited patients and families to complete an experience of care survey. This paper reports the positive attributes and the opportunities for improvement in CF care from the perspective of individuals with CF and families. Methods Patients and families completed the survey by web, interactive voice response, or with the help of a telecommunication professional. Funnel plot was used to determine positive attributes and improvement opportunities. Chi-square tests and 95% confidence intervals were used to determine differences between group and logistic regression models were used to determine factors associated with the experience of "best" care. Results 2090 adults with CF or parents of children with CF, 29% of the 7113 potential respondents, completed a survey. Both the adult and pediatric survey respondents reported the same 5 positive attributes of experience of care: courtesy and respect shown, easy to understand explanations, involved in decision-making, their questions were answered, and enough time with providers. Potential areas for improvement included assessing mental health and improving inpatient hospital staff's knowledge of CF. In general, results from the pediatric survey were significantly better than the adult survey. Variables predictive of "best" care experience from both adult and pediatric respondents were treatments always working and two self-care factors of finding information and working out solutions. Conclusion The CF Foundation developed an experience of care survey to systematically collect and learn directly from individuals with CF and families about their impressions and observations of CF health care delivery. Respondents reported positive and respectful experiences and improvement opportunities were identified, which can help programs target specific areas to enhance the care experience.

BACKGROUND AND OBJECTIVES: Cystic fibrosis transmembrane conductance regulator–related metabolic syndrome (CRMS) describes asymptomatic infants with a positive cystic fibrosis (CF) newborn screen (NBS) but inconclusive diagnostic testing for CF. Little is known about the epidemiology and outcomes of CRMS. The goal of this study was to determine the prevalence, clinical features, and short-term outcomes of infants with CRMS. METHODS: We analyzed data from the US CF Foundation Patient Registry (CFFPR) from 2010 to 2012. We compared demographic, diagnostic, anthropometric, health care utilization, microbiology, and treatment characteristics between infants with CF and infants with CRMS. RESULTS: There were 1983 infants diagnosed via NBS between 2010 and 2012 reported to the CFFPR. By using the CF Foundation guideline definitions, 1540 and 309 infants met the criteria for CF and CRMS, respectively (CF:CRMS ratio = 5.0:1.0). Of note, 40.8% of infants with CRMS were entered into the registry with a clinical diagnosis of CF. Infants with CRMS tended to have normal nutritional indices. However, 11% of infants with CRMS had a positive Pseudomonas aeruginosa respiratory tract culture in the first year of life. CONCLUSIONS: CRMS is a common outcome of CF NBS, and some infants with CRMS may develop features concerning for CF disease. A substantial proportion of infants with CRMS were assigned a clinical diagnosis of CF, which may reflect misclassification or clinical features not collected in the CFFPR.

Background Treatment of pulmonary exacerbations (PEx) in cystic fibrosis (CF) varies widely with no consensus on management practices or best indicators of therapeutic success. To design trials evaluating PEx treatment factors, we characterise the heterogeneity of PEx care in adults and paediatrics, and correlate it with measures of clinical response including short-term and long-term lung function changes, change in symptom severity score and time to next intravenous antibiotic therapy. Methods Data were used from a prospective observational study of patients with CF ≥10 years of age enrolled at six sites between 2007 and 2010. All were started on intravenous antibiotics for a clinically diagnosed PEx. Analysis of variance, logistic and Cox regression were used to examine the association of treatment factors with short-term and long-term clinical response. Results Of 123 patients with CF (60% women, aged 23.1±10.2 years), 33% experienced 1 during treatment, which was associated with failing to recover baseline lung function 3 months after treatment (OR=7.8, 95% CI 1.9 to 31.6, p=0.004) and a longer time to next intravenous antibiotic (HR=0.48, 95% CI 0.27 to 0.85, p=0.011). Symptom improvement was observed but was not associated with subsequent lung function or time to next antibiotic therapy, which had a median recurrence time of 143 days. Conclusions Immediate symptomatic or respiratory response to PEx treatment did not have a clear relationship with subsequent outcomes such as lung function or intravenous antibiotic-free interval. These results can inform future research of treatment regimens for PEx in terms of interventions and outcome measures. Trial registration NCT00788359 (www.clinicaltrials.gov).

SummaryObjectives The purpose of this study was to characterize the utilization of antibiotics for chronic methicillin-resistant Staphylococcus aureus (MRSA) infection in cystic fibrosis (CF) patients with acute pulmonary exacerbations (PEx). Methods An anonymous national cross-sectional survey of CF Foundation accredited care programs was performed using an electronic survey tool. Results Fifty-eight percent (152/261) CF Foundation accredited programs completed the survey. Ninety-eight percent (149/152) of respondents reported using antibiotics (oral or intravenous) against MRSA. Variability exists in the use of antibiotics amongst the programs and in the dosages utilized. For oral outpatient treatment, sulfamethoxazole/trimethoprim was the most commonly utilized antibiotic by both pediatric (109/287, 38%) and adult (99/295, 34%) respondents, of which, ten percent of reported to use it in combination with rifampin. For inpatient treatment, linezolid (both intravenous (IV) and oral) was most commonly utilized in both pediatric (IV 35/224, 16%; oral 41/224, 18%), and adult (IV 44/235, 19%; oral 38/235, 16%) respondents for inpatient treatment. IV vancomycin was the second most commonly utilized antibiotic by pediatric (70/224, 31%) and adult (71/235, 30%) respondents. Most respondents reported dose titration to achieve a vancomycin trough level of 15–20 mg/L (150/179, 84%). Topical or inhaled antibiotic utilization was reported to be an uncommon practice with approximately 70% of pediatric and adult respondents reporting to use them either rarely or never. The concomitant use of anti-MRSA and anti-pseudomonal antibiotics was common with 96% of pediatric and 99% of adult respondents answering in the affirmative. Conclusion We conclude that anti-MRSA antibiotics are utilized via various dosage regimens by a majority of CF Foundation accredited care programs for the treatment of chronic MRSA in PEx, and there is no consensus on the best treatment approach. Pediatr Pulmonol. 2015; 50:552–559. © 2015 Wiley Periodicals, Inc.

The Cystic Fibrosis (CF) Foundation developed clinical care guidelines for the prevention of Pseudomonas aeruginosa infection, the treatment of initial P. aeruginosa infection, and the use of bronchoscopy to obtain routine airway cultures in individuals with CF.A multidisciplinary committee developed questions about the prevention and treatment of initial P. aeruginosa infection and the use of bronchoscopy to obtain routine airway cultures. The outcome measure of interest was cultures without P. aeruginosa growth. Systematic reviews of PubMed, EMBASE, and the Cochrane Central Register of Controlled Trials were conducted in May 2012 and August 2013. Searches combined controlled vocabulary terms and text words for CF and terms relevant to each question. The entire committee reviewed the evidence, and final recommendation statements were graded using the U.S. Preventive Services Task Force system. Recommendation 1: The CF Foundation strongly recommends inhaled antibiotic therapy for the treatment of initial or new growth of P. aeruginosa from an airway culture (certainty of net benefit, high; estimate of net benefit, substantial; grade of recommendation, A). The favored antibiotic regimen is inhaled tobramycin (300 mg twice daily) for 28 days. Recommendation 2: The CF Foundation recommends against the use of prophylactic antipseudomonal antibiotics to prevent the acquisition P. aeruginosa (certainty of net benefit, moderate; estimate of net benefit, zero; grade of recommendation, D). Recommendation 3: The CF Foundation recommends routine oropharyngeal cultures rather than bronchoalveolar lavage cultures obtained by bronchoscopy in individuals with CF who cannot expectorate sputum to determine if they are infected with P. aeruginosa (certainty of net benefit, moderate; estimate of net benefit, moderate; grade of recommendation, B).

There are many challenges to providing end-of-life care (EOLC) to people with cystic fibrosis (CF).Chart abstraction was used to examine EOLC in adults with CF who died between 2011 and 2013.We reviewed 248 deaths from 71 CF care centers. Median age at death was 29years (range 18-73). While median FEV1 was in the severe lung disease category (FEV140%), 38% had mild or moderate lung disease in the year preceding death. The most common location of death was the intensive care unit (ICU, 39%), and 12% of decedents were listed for lung transplant. Fewer of those dying in the ICU personally participated in advance care planning or utilized hospice or Palliative Care Services (p0.05).Adults dying with CF in the United States most commonly die in an ICU, with limited and variable use of hospice and Palliative Care Services. Palliative care and advance care planning are recommended as a routine part of CF care.

Background In 2011, the median age of survival of patients with cystic fibrosis reported in the United States was 36.8 years, compared with 48.5 years in Canada. Direct comparison of survival estimates between national registries is challenging because of inherent differences in methodologies used, data processing techniques, and ascertainment bias. Objective To use a standardized approach to calculate cystic fibrosis survival estimates and to explore differences between Canada and the United States. Design Population-based study. Setting 42 Canadian cystic fibrosis clinics and 110 U.S. cystic fibrosis care centers. Patients Patients followed in the Canadian Cystic Fibrosis Registry (CCFR) and U.S. Cystic Fibrosis Foundation Patient Registry (CFFPR) between 1990 and 2013. Measurements Cox proportional hazards models were used to compare survival between patients followed in the CCFR (n = 5941) and those in the CFFPR (n = 45 448). Multivariable models were used to adjust for factors known to be associated with survival. Results Median age of survival in patients with cystic fibrosis increased in both countries between 1990 and 2013; however, in 1995 and 2005, survival in Canada increased at a faster rate than in the United States (P < 0.001). On the basis of contemporary data from 2009 to 2013, the median age of survival in Canada was 10 years greater than in the United States (50.9 vs. 40.6 years, respectively). The adjusted risk for death was 34% lower in Canada than the United States (hazard ratio, 0.66 [95% CI, 0.54 to 0.81]). A greater proportion of patients in Canada received transplants (10.3% vs. 6.5%, respectively [standardized difference, 13.7]). Differences in survival between U.S. and Canadian patients varied according to U.S. patients' insurance status. Limitation Ascertainment bias due to missing data or nonrandom loss to follow-up might affect the results. Conclusion Differences in cystic fibrosis survival between Canada and the United States persisted after adjustment for risk factors associated with survival, except for private-insurance status among U.S. patients. Differential access to transplantation, increased posttransplant survival, and differences in health care systems may, in part, explain the Canadian survival advantage. Primary Funding Source U.S. Cystic Fibrosis Foundation.

Objective Cystic fibrosis (CF), caused by mutations in the CF transmembrane conductance regulator ( CFTR ) gene, continues to present diagnostic challenges. Newborn screening and an evolving understanding of CF genetics have prompted a reconsideration of the diagnosis criteria. Study design To improve diagnosis and achieve standardized definitions worldwide, the CF Foundation convened a committee of 32 experts in CF diagnosis from 9 countries to develop clear and actionable consensus guidelines on the diagnosis of CF and to clarify diagnostic criteria and terminology for other disorders associated with CFTR mutations. An a priori threshold of ≥80% affirmative votes was required for acceptance of each recommendation statement. Results After reviewing relevant literature, the committee convened to review evidence and cases. Following the conference, consensus statements were developed by an executive subcommittee. The entire consensus committee voted and approved 27 of 28 statements, 7 of which needed revisions and a second round of voting. Conclusions It is recommended that diagnoses associated with CFTR mutations in all individuals, from newborn to adult, be established by evaluation of CFTR function with a sweat chloride test. The latest mutation classifications annotated in the Clinical and Functional Translation of CFTR project (http://www.cftr2.org/index.php) should be used to aid in diagnosis. Newborns with a high immunoreactive trypsinogen level and inconclusive CFTR functional and genetic testing may be designated CFTR - related metabolic syndrome or CF screen positive, inconclusive diagnosis; these terms are now merged and equivalent, and CFTR - related metabolic syndrome/CF screen positive, inconclusive diagnosis may be used. International Statistical Classification of Diseases and Related Health Problems, 10th Revision codes for use in diagnoses associated with CFTR mutations are included.

Bringing new therapies to patients with rare diseases depends in part on optimizing clinical trial conduct through efficient study start-up processes and rapid enrollment. Suboptimal execution of clinical trials in academic medical centers not only results in high cost to institutions and sponsors, but also delays the availability of new therapies. Addressing the factors that contribute to poor outcomes requires novel, systematic approaches tailored to the institution and disease under study.To use clinical trial performance metrics data analysis to select high-performing cystic fibrosis (CF) clinical research teams and then identify factors contributing to their success.Mixed-methods research, including semi-structured qualitative interviews of high-performing research teams.CF research teams at nine clinical centers from the CF Foundation Therapeutics Development Network.Survey of site characteristics, direct observation of team meetings and facilities, and semi-structured interviews with clinical research team members and institutional program managers and leaders in clinical research.Critical success factors noted at all nine high-performing centers were: 1) strong leadership, 2) established and effective communication within the research team and with the clinical care team, and 3) adequate staff. Other frequent characteristics included a mature culture of research, customer service orientation in interactions with study participants, shared efficient processes, continuous process improvement activities, and a businesslike approach to clinical research.Clinical research metrics allowed identification of high-performing clinical research teams. Site visits identified several critical factors leading to highly successful teams that may help other clinical research teams improve clinical trial performance.

Objective Preparation of this supplement, Ten years of improvement innovation in cystic fibrosis care , tested a strategy to support writing and scholarly publication by cystic fibrosis (CF) healthcare improvement professionals. Intervention Critical elements of the writing initiative included: a request for abstracts that was distributed to over 2000 professionals in the Cystic Fibrosis Foundation-supported improvement community to identify promising work; continuous peer review of manuscripts by co-authors and writing tutors; three webinars and a 2-day face-to-face writing retreat that addressed the challenges of successful scholarly healthcare improvement writing and publication; and finally, journal submission and formal external peer review. The SQUIRE Publication Guidelines provided content framework for manuscripts. Results 47 abstracts were submitted from which reviewers selected nine for participation. The 28 co-authors of these abstracts took part in the writing initiative. Authors’ self-assessment showed that half had previously published fewer than five papers, while 80% considered themselves insufficiently prepared to write for the scholarly improvement literature. Eventually all of the nine abstracts led to full manuscripts, which were submitted to the journal for formal peer review. Of these, seven were accepted for publication and are included in this supplement. Conclusions A formal initiative to develop and support scholarly writing—while resource-intensive—offers opportunities for wider publication by healthcare improvement professionals.

Context: Scientific and therapeutic advances Remarkable biomedical research advances have led to innovative and increasingly effective therapies. We highlight several scientific milestones in elucidating the pathophysiology of cystic fibrosis (CF) and review the therapies that have become available over the past 20 years. Impact of the quality improvement initiative In 2002, the CF Foundation launched a multifaceted quality improvement initiative to accelerate improvement in CF care. We present evidence of substantial improvement in process measures, such as more consistent outpatient follow-up, and key medical outcomes, including survival, pulmonary function and nutritional status. Critical success factors We offer our perspective on factors critical to the success of the quality improvement initiative, including a compelling strategic plan and the commitment of the CF Foundation to its implementation; the investment in building improvement capacity at CF care centres; the engagement of people with CF and their families as partners; and the integration of quality improvement into the existing CF care framework. Directions for the next decade In addition to a continued investment in building and sustaining improvement capacity at CF care centres, and deeper patient engagement, we will address the oppressive treatment burden. We will also complement the measurement of clinical outcomes with patient reported outcomes and healthcare costs for a balanced assessment of the quality and value of care. Conclusions Major advances in basic science and therapeutic development coupled with improvements in healthcare delivery have resulted in striking gains in medical outcomes for people with CF.

Benchmarking is the process of using outcome data to identify high-performing centres and determine practices associated with their outstanding performance. The US Cystic Fibrosis Foundation (CFF) Patient Registry contains centre-specific outcomes data for all CFF-certified paediatric and adult cystic fibrosis (CF) care programmes in the USA. The CFF benchmarking project analysed these registry data, adjusting for differences in patient case mix known to influence outcomes, and identified the top-performing US paediatric and adult CF care programmes for pulmonary and nutritional outcomes. Separate multidisciplinary paediatric and adult benchmarking teams each visited 10 CF care programmes, five in the top quintile for pulmonary outcomes and five in the top quintile for nutritional outcomes. Key practice patterns and approaches present in both paediatric and adult programmes with outstanding clinical outcomes were identified and could be summarised as systems, attitudes, practices, patient/family empowerment and projects. These included: (1) the presence of strong leadership and a well-functioning care team working with a systematic approach to providing consistent care; (2) high expectations for outcomes among providers and families; (3) early and aggressive management of clinical declines, avoiding reliance on 'rescues'; and (4) patients/families that were engaged, empowered and well informed on disease management and its rationale. In summary, assessment of practice patterns at CF care centres with top-quintile pulmonary and nutritional outcomes provides insight into characteristic practices that may aid in optimising patient outcomes.

Objective: To review current approaches for obtaining patient data in Duchenne muscular dystrophy (DMD) and consider how monitoring and comparing outcome measures across DMD clinics could facilitate standardized and improved patient care. Methods: We reviewed annual standardized data from cystic fibrosis (CF) clinics and DMD care guidelines and consensus statements; compared current approaches to obtain DMD patient data and outcome measures; and considered the best method for implementing public reporting of outcomes, to drive improvements in health care delivery. Results: Current methods to monitor DMD patient information (MD STARnet, DuchenneConnect, and TREAT-NMD) do not yet provide patients with comparative outcome data. The CF patient registry allows for reporting of standard outcomes across clinics and is associated with improved CF outcomes. A similar patient registry is under development for the Muscular Dystrophy Association (MDA) clinic network. Suggested metrics for quality care include molecular diagnosis, ambulatory status and age at loss of ambulation, age requiring ventilator support, and survival. Conclusions: CF longevity has increased by almost 33% from 1986 to 2010, in part due to a CF patient registry that has been stratified by individual care centers since 1999, and publically available since 2006. Implementation of outcome reporting for MDA clinics might promote a similar benefit to patients with DMD.

Background Many patients with cystic fibrosis (CF) now reach adulthood, at which time the risk of cancer is increased. The aim of this study was to determine cancer risks in nontransplanted and transplanted CF patients. Methods From 1990 to 2009, we followed 41,188 patients who received care at one of the 250 CF care center programs in the United States and compared the observed number of cancers in nontransplanted and transplanted patients with that expected in the general US population. Results In 344,114 patient-years of observation of nontransplanted patients, the overall cancer risk was similar to the background risk (standardized incidence ratio [SIR] = 1.1, 95% confidence interval [CI] = 1.0 to 1.3). However, we observed an elevated risk of digestive tract cancer (SIR = 3.5, 95% CI = 2.6 to 4.7) involving the esophago-gastric junction, biliary tract, small bowel, and colon. There was also an increased risk of testicular cancer (SIR = 1.7, 95% CI = 1.02 to 2.7) and lymphoid leukemia (SIR = 2.0, 95% CI = 1.2 to 3.1) and a decreased risk of malignant melanoma (SIR = 0.4, 95% CI = 0.2 to 0.9). In 8235 patient-years of observation of transplanted patients, 26 tumors were observed compared with 9.6 expected (SIR = 2.7, 95% CI = 1.8 to 3.9). The increased risk was particularly high for digestive tract cancers (SIR = 17.3, 95% CI = 10.7 to 26.5), with most cases arising in the bowel. Conclusions The overall burden of cancer in CF patients remains low; however they have an increased risk of digestive tract cancer, particularly following transplantation. They also have increased risk of lymphoid leukemia and testicular cancer, and decreased risk of melanoma.

Nutrition is integral to the care of individuals with cystic fibrosis (CF). Better nutritional status is associated with improved pulmonary function. In some individuals with CF, enteral tube feeding can be useful in achieving optimal nutritional status. Current nutrition guidelines do not include detailed recommendations for enteral tube feeding. The Cystic Fibrosis Foundation convened an expert panel to develop enteral tube feeding recommendations based on a systematic review of the evidence and expert opinion. These guidelines address when to consider enteral tube feeding, assessment of confounding causes of poor nutrition in CF, preparation of the patient for placement of the enteral feeding tube, management of the tube after placement and education about enteral feeding. These recommendations are intended to guide the CF care team, individuals with CF, and their families through the enteral tube feeding process.

BACKGROUND: Previous studies demonstrated increased digestive tract cancers among individuals with cystic fibrosis (CF), particularly among lung transplant recipients. We describe cancer incidence among CF and non-CF lung recipients. METHODS: We used data from the US transplant registry and 16 cancer registries. Standardized incidence ratios (SIRs) compared cancer incidence to the general population, and competing risk methods were used for the cumulative incidence of colorectal cancer. RESULTS: We evaluated 10,179 lung recipients (1,681 with CF). Risk was more strongly increased in CF recipients than non-CF recipients for overall cancer (SIR 9.9 vs. 2.7) and multiple cancers including colorectal cancer (24.2 vs. 1.7), esophageal cancer (56.3 vs. 1.3), and non-Hodgkin lymphoma (61.8 vs. 9.4). At five years post-transplant, colorectal cancer was diagnosed in 0.3% of CF recipients aged