US Cystic Fibrosis Foundation Research Articles

Impact of age at ivacaftor initiation on pulmonary outcomes among people with cystic fibrosis

BackgroundIvacaftor (IVA) improves lung function and other extrapulmonary outcomes in people with cystic fibrosis (CF). However, the effect of initiating IVA at earlier versus later ages has not been studied.MethodsWe...

Longitudinal bacterial prevalence in cystic fibrosis airways: Fact and artifact

BackgroundOpportunistic bacterial infection is a hallmark of cystic fibrosis (CF) lung disease and early mortality. Poorly characterized prevalence changes have accompanied two decades of health improvements, with CFTR modulators likely to further affect infection epidemiology. MethodsBacterial prevalence change trends across birth cohorts were assessed with linear regression using 2001–2019 US CF Foundation Patient Registry data. Informative missingness was assessed, as was age-to-age infection status. ResultsBacterial prevalence constantly changed from 2001 to 2019, with changes differing across birth cohorts. Informative censoring affected prevalence change for some organisms. Age-to-age infection status changes were greater than net changes in bacterial prevalence and varied by age. ConclusionsCF infection epidemiology changed over two decades and will continue to do so. Understanding how modulators affect infection epidemiology will require creative designs for longitudinal prevalence change studies emphasizing prevalence changes independent of effects on lung biology.

Cystic fibrosis survival outcomes following second lung transplant: The north American experience.

Re-transplant is an option for those who develop end-stage lung disease due to rejection; however, little data exist following re-transplantation in cystic fibrosis (CF). Data from the Canadian CF Registry and US CF Foundation Patient Registry supplemented with data from United Network for Organ Sharing were used. Individuals who underwent a 2nd lung transplant between 2005 and 2019 were included. The Kaplan-Meier method was used to estimate the probability of survival post-second transplant at 1, 3, and 5-years. Of those people who were waitlisted for a second transplant (N=818), a total of 254 (31%) died waiting, 395 (48%) were transplanted and 169 (21%) people were alive on the waitlist. Median survival time after 2nd lung transplant was 3.3 years (95% CI: 2.8-4.1). The 1-, 3- and 5-year survival rates were 77.4% (95% CI: 73.1-82%), 52% (95% CI: 46.7-58%) and 39.4% (95% CI: 34.1-45.6%). Survival following second lung transplant in CF patients is lower than estimates following the first transplant. Over half of subjects who are potentially eligible for a second transplant die without receiving a second organ. This warrants further investigation.

Multilevel joint model of longitudinal continuous andbinary outcomes for hierarchically structured data.

Joint modeling has been a useful strategy for incorporating latent associations between different types of outcomes simultaneously, often focusing on a longitudinal continuous outcome characterized by an LME submodel and a terminal event subject to a Cox proportional hazard or parametric survival submodel. Applications to hierarchical longitudinal studies have been less frequent, particularly with respect to a binary process, which is commonly specified by a GLMM. Furthermore, many of the joint model developments have not allowed for investigations of nested effects, such as those arising from multicenter studies. To fill this gap, we propose a multilevel joint model that encompasses the LME submodel and GLMM through a Bayesian approach. Motivated by the need for timely detection of pulmonary exacerbation and characterization of irregularly observed lung function measurements in people living with cystic fibrosis (CF) receiving care across multiple centers, we apply the model to the data arising from US CF Foundation Patient Registry. In parallel, we examine the extent of bias induced by a non-hierarchical model. Our simulation study and application results show that incorporating the center effect along with individual stochastic variation over time within the LME submodel improves model estimation and prediction. Given that the center effect is evident in lung function observed in the CF population, accounting for center-specific power parameters by incorporating the symmetric power exponential power (spep) link function in the GLMM can facilitate more accurate conclusions in clinical studies.

Registry-based study in people with cystic fibrosis and an R117H variant treated with ivacaftor

BackgroundIvacaftor approval was extended to people with cystic fibrosis (CF) and an R117H variant in 2014 in the USA. This observational, real-world, postapproval study evaluated long-term outcomes among people with...

Real-world safety and effectiveness of elexacaftor/tezacaftor/ivacaftor in people with cystic fibrosis: Interim results of a long-term registry-based study

BackgroundPhase 3 clinical trials showed elexacaftor/tezacaftor/ivacaftor (ELX/TEZ/IVA) was safe and efficacious in people with cystic fibrosis (CF) with ≥1 F508del-CFTR allele. To assess long-term effects of ELX/TEZ/IVA under real-world conditions of use, a 5-year observational registry-based study is being conducted. We report interim results from the first 2 years of follow-up. MethodsThe study included people with CF in the US Cystic Fibrosis Foundation Patient Registry (CFFPR) who initiated ELX/TEZ/IVA between October 2019 and December 2020. Pulmonary exacerbations (PEx), percent predicted forced expiratory volume in 1 second (ppFEV1), hospitalizations, bacterial pathogens, body mass index (BMI), CF complications and comorbidities, and liver function tests (LFTs) after treatment initiation were compared with the 5-year pre-treatment period. Death and lung transplantation were assessed relative to 2019 CFFPR data. Results16,116 people with CF were included (mean treatment duration 20.4 months). Among those with 5 years of pre-treatment data, mean PEx/patient/year declined to 0.18 (95% CI: 0.17, 0.19) in Years 1 and 2 post-treatment from 0.86 (95% CI: 0.83, 0.88) in the baseline year (79% reduction), after a continued increase observed pre-treatment. Similarly, a decline in mean hospitalizations/patient/year was observed in Year 1 that was sustained in Year 2 (74% reduction from baseline year). The mean absolute change in ppFEV1 from baseline was +8.2 percentage points (95% CI: 8.0, 8.4) in Year 1 and +8.9 percentage points (95% CI: 8.7, 9.1) in Year 2, after a continued decline observed pre-treatment. Positive bacterial cultures decreased for all evaluated pathogens, and mean BMI increased by 1.6 kg/m2 (95% CI: 1.5, 1.6) by Year 2. No new safety concerns were identified based on evaluation of CF complications, comorbidities, and LFTs. The annualized rates of death (0.47% [95% CI: 0.39, 0.55]) and lung transplantation (0.16% [95% CI: 0.12, 0.22]) were considerably lower than reported in 2019 (1.65% and 1.08%, respectively). ConclusionsELX/TEZ/IVA treatment was associated with sustained improvements in lung function, reduced frequency of PEx and all-cause hospitalization, increased BMI, and lower prevalence of positive bacterial cultures. Additionally, there was a 72% lower rate of death and 85% lower rate of lung transplantation relative to the year before ELX/TEZ/IVA availability. These results, from the largest cohort of ELX/TEZ/IVA-treated people to date, extend our understanding of the broad clinical benefits of ELX/TEZ/IVA.

Early life growth trajectories in cystic fibrosis are associated with lung function at age six

BackgroundHigher growth percentiles are associated with more favorable lung function in cystic fibrosis (CF), prompting the creation of CF Foundation (CFF) nutritional guidelines. ObjectivesTo describe early childhood growth trajectories within CF, to determine if growth trajectories are associated with differences in lung function at age six, and to identify factors that differ between trajectory groups. MethodsRetrospective cohort study of children diagnosed with CF and born 2000–2011 using the US CFF Patient Registry. Annualized growth parameters prior to age six were included in group-based trajectory modeling to identify unique early life growth trajectories. FEV1 percent predicted (FEV1pp) at age six was compared between trajectory groups using linear regression. Factors associated with group membership were identified using multinomial logistic regression. Results6,809 children met inclusion criteria. Six discrete growth trajectories were identified, including three groups that began with growth parameters >50th percentile, termed: “always high”, “gradual decliner”, “rapid decliner”, and three which began with growth parameters <50th percentile, termed: “rapid riser”, “gradual riser”, “always low”. FEV1pp at age six was highest for the Always High trajectory. The Always Low trajectory was nearly 10% lower than the Always High trajectory. Sex, ethnicity, newborn screening and pancreatic function were associated with trajectory class membership. ConclusionsDistinct early life growth trajectories were identified within CF. Trajectories that met CFF nutritional guideline recommendations were associated with higher FEV1pp at age six. CF care teams should continue to partner with families to encourage interventions to support optimal growth to improve lung function in CF.

EFFECT OF ELEXACAFTOR/TEZACAFTOR/IVACAFTOR ON ANNUAL RATE OF LUNG FUNCTION DECLINE IN PEOPLE WITH CYSTIC FIBROSIS

Elexacaftor/tezacaftor/ivacaftor (ELX/TEZ/IVA) was shown to be safe and efficacious in people with cystic fibrosis (CF) with ≥ 1 F508del-CFTR allele in Phase 3 clinical trials. ELX/TEZ/IVA treatment led to improved lung function, with increases in percent predicted forced expiratory volume in 1second (ppFEV1) and Cystic Fibrosis Questionnaire-Revised respiratory domain score. Here, we evaluated the impact of ELX/TEZ/IVA on the rate of lung function decline over time by comparing changes in ppFEV1 in participants from the Phase 3 trials with a matched group of people with CF from the US Cystic Fibrosis Foundation Patient Registry not eligible for cystic fibrosis transmembrane conductance regulator (CFTR) modulator therapy. Participants treated with ELX/TEZ/IVA had on average no loss of pulmonary function over a 2-year period (mean annualized rate of change in ppFEV1, +0.39 percentage points [95% CI, -0.06 to 0.85]) compared with a 1.92 percentage point annual decline (95% CI, -2.16 to -1.69) in ppFEV1 in untreated controls. ELX/TEZ/IVA is the first CFTR modulator therapy shown to halt lung function decline over an extended time period.

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

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

Genetic factors help explain the variable responses of young children with cystic fibrosis to vitamin D supplements.

Children with cystic fibrosis (CF) are susceptible to fat-soluble vitamin deficiencies unless supplemented, but even large doses of vitamin D may not prevent low 25-hydroxyvitamin D (25OHD) concentrations. The explanation for these vitamin D non-responders has been elusive. We utilized data from whole genome sequencing (WGS) to test the hypothesis that genetic variations predict responsiveness to vitamin D supplementation in a prospective cohort study of children with CF in the first 3 years of life. One hundred and one infants born during 2012-2017 and diagnosed with CF through newborn screening were studied. Serum 25OHD concentrations and vitamin D supplement doses were assessed during early infancy and annually thereafter. WGS was performed, the resultant variant calling files processed, and the summary statistics from a recent genome-wide association study were utilized to construct a polygenic risk score (PRS) for each subject. Overall, the prevalence of vitamin D insufficiency (<30ng/mL) was 21% in the first 3 years of life. Among the 70 subjects who always adhered to vitamin D supplement doses recommended by the US CF Foundation guidelines, 89% were responders (achieved vitamin D sufficiency) by 3 years of age, while 11% were transient or non-responders. Multiple regression analysis revealed that PRS was a significant predictor of 25OHD concentrations (p<0.001) and the likelihood of being an earlier responder in the first 3 years of life (p<0.01). A limited SNP analysis revealed variants in four important genes (GC, LIPC, CYP24A1, and PDE3B) that were shown to be associated with 25OHD concentrations and vitamin D responder status. Other determinants included vitamin D supplement dose, season at 25OHD measurement, and pancreatic functional status. Applying WGS in conjunction with utilizing a PRS approach revealed genetic variations that partially explain the unresponsiveness of some children with CF to vitamin D supplementation. Our findings suggest that a nutrigenomics strategy could help promote personalized treatment in CF.

P071 The characterisation of a patient cohort that had home spirometry devices and opted into sharing their data with the US Cystic Fibrosis Foundation

P071 The characterisation of a patient cohort that had home spirometry devices and opted into sharing their data with the US Cystic Fibrosis Foundation

Obesity in Cystic fibrosis: prevalence, trends and associated factors data from the US cystic fibrosis foundation patient registry

Strong emphasis has been placed historically on increasing weight and improving nutritional status in cystic fibrosis patients. Due to correlation between nutritional indices (e.g. BMI) and lung function, CF Nutrition Guidelines have recommended BMI percentile goals at the 50th percentile or higher. Trends in increasing BMI across CF programs suggest significantly increasing proportions of overweight and obese status in recent years. We identify that between 2000 and 2019 there has been a relative decrease in underweight status by ∼40%, simultaneously with a > 300% increase in overweight status, and >400% increase in obesity. Patient specific factors associated with higher prevalence of obesity included age ≥46, living in a zip code where the median income was < $20,000, having at least one allele with a class IV or V mutation, a ppFEV1 >90 prescribed ivacaftor, and not prescribed pancreatic enzymes. Program specific factors were not identified.

CFTR modulator use and risk of nontuberculous mycobacteria positivity in cystic fibrosis, 2011-2018.

BackgroundPeople with cystic fibrosis are at increased risk of pulmonary nontuberculous mycobacteria (NTM) disease. Cystic fibrosis transmembrane conductance regulator (CFTR) modulators are associated with reduced lung infection with pathogens like Pseudomonas aeruginosa and Staphylococcus aureus. This association has not been studied with NTM.MethodsUsing encounter-level data from the US Cystic Fibrosis Foundation Patient Registry from 2011 to 2018, we identified individuals aged >12 years with one or more NTM-negative sputum culture and information on receipt of ivacaftor therapy. We used a Cox proportional hazards model to assess the relationship between CFTR modulator usage (any and monotherapy versus combination therapy) and NTM sputum culture positivity, controlling for sex, least severe class of CFTR mutation, receipt of chronic macrolides, age, body mass index and percentage predicted forced expiratory volume.ResultsOut of 25 987 unique individuals, 17 403 individuals met inclusion criteria. During follow-up, 42% of individuals received CFTR modulator therapy, and 23% had incident NTM. The median (interquartile range) time to event was 6.1 (4.0–7.3) years for those ever receiving CFTR modulators compared to 4.0 (1.6–6.5) years in those never receiving CFTR modulators. CFTR modulator use was associated with a significantly reduced hazard of NTM culture positivity (hazard ratio (HR) 0.88, 95% CI 0.79–0.97); there was no significant difference in the hazard between those receiving ivacaftor monotherapy versus combination therapy (combination HR 1.01, 95% CI 0.79–1.23).ConclusionsCFTR modulator therapy is associated with a decreased risk of NTM positivity in individuals with cystic fibrosis.

Sustained Reduction in Time to Data Entry in the Cystic Fibrosis Foundation Registry.

Introduction:Timely data entry into patient registries is foundational to learning health systems such as the Cystic Fibrosis Learning Network. The US Cystic Fibrosis Foundation Patient Registry (CFFPR) is an established registry that collects encounter data for clinical and research activities. Coordinators manually enter approximately 1,500 encounters annually at our institution, but there is limited evidence for interventions facilitating timely data entry. Our institution aimed to reduce the number of days between a clinical encounter and data entry into the CFFPR from an average of 43 days (range 0 to 183 days) to less than 30 days in a 3-month interval.Methods:Data coordinators tested interventions to address barriers in four themes: accountability, work burden, communication, and visibility using plan-do-study-act cycles. We used statistical process control charts to assess progress on average time of entry. Coordinators provided feedback about acceptability and satisfaction for process changes.Results:Initial interventions standardized process and reduced average time to data entry from 42.6 to 22.5 days in 3 months, but this process was not stable in the subsequent 6 months. Subsequent changes to increase metric visibility and improve team communication increased stability and decreased the average time to data entry to 23.0 days. Coordinators reported high satisfaction with process changes and have sustained improved time for over 2 years.Conclusions:This quality improvement project reduced and maintained data entry time by addressing significant barriers without additional personnel. Increased access to near real-time data in CFFPR accelerates learning for clinical care, quality improvement, and research.

Burden of cystic fibrosis in children

BackgroundCystic fibrosis (CF) is a genetic, multisystemic, progressive and life-shortening disease caused by mutations in the CF transmembrane conductance regulator (CFTR) gene. Different genotypes have been linked to variations in...

Disease burden in people with cystic fibrosis heterozygous for F508del and a minimal function mutation

BackgroundPeople with cystic fibrosis (CF) heterozygous for F508del-CFTR and a minimal function CFTR mutation (F/MF) that results in no CFTR protein or results in CFTR protein that is not responsive to tezacaftor, ivacaftor, and tezacaftor/ivacaftor in vitro comprise a sizeable percentage of the US CF population. This retrospective, cross-sectional, observational study aimed to characterize CF burden in this subpopulation. MethodsPeople ≥2 years of age in the US CF Foundation Patient Registry with a CF diagnosis, F/MF genotype, and ≥1 encounters in 2017 were included. Descriptive analyses assessed lung function, nutritional parameters, microbiology, hospitalization and pulmonary exacerbation rates, and CF-related complications. Results were stratified by age group; select characteristics were summarized by percent predicted FEV1 (ppFEV1) and ethnicity. Results5348 people met inclusion criteria. Rates of positive bacterial cultures, pulmonary exacerbations, and hospitalizations were generally higher in older age groups. Prevalence of prescribed symptomatic CF therapies was substantial and also generally higher in older age groups. ppFEV1 was lower in older age groups. A greater percentage of adolescents and adults reported complications, including cirrhosis, osteoporosis, osteopenia, and sinus disease, than younger age groups. Increased prevalence of cultured Pseudomonas aeruginosa and prescribed chronic therapy was seen with decreasing ppFEV1. In each age group, ppFEV1 was slightly higher in the non-Hispanic cohort than in the Hispanic cohort. ConclusionsPeople with F/MF genotypes have substantial disease burden that worsened in older age groups consistent with the progressive nature of CF, indicating need for additional treatment options in this subpopulation.

Survival models to support shared decision-making about advance care planning for people with advanced stage cystic fibrosis

BackgroundFor people with advanced stage cystic fibrosis (CF), tailored survival estimates could facilitate preparation for decision-making in the event of acutely deteriorating respiratory function.MethodsWe used the US CF Foundation national...

Survival and Lung Transplant Outcomes for Individuals With Advanced Cystic Fibrosis Lung Disease Living in the United States and Canada: An Analysis of National Registries

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. What are rates of lung transplant (LTx) and rates of death without LTx in the United States and Canada among individuals with FEV1< 40%predicted? 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< 40%predicted within a 5-year period, age≥ 6 years, without prior LTx were included. Multivariable competing risk regression for time to death without LTx (LTx as a competing risk) and time to LTx (death as a competing risk) was performed. There were 5,899 patients (53%male) and 905 patients (54%male) with CF with FEV1< 40%predicted living in the United States and Canada, respectively. Multivariable competing risk regression models identified an increased risk of death without LTx (hazard ratio [HR], 1.79; 95%CI, 1.52-2.1) and decreased LTx (HR, 0.66; 95%CI, 0.58-0.74) among individuals in the United States compared with Canada. More pronounced differences were seen in the patients in the United States with Medicaid/Medicare insurance compared with Canadians (multivariable HR for death without LTx, 2.24 [95%CI, 1.89-2.64]; multivariable HR for LTx, 0.54 [95%CI, 0.47-0.61]). Patients of nonwhite race were also disadvantaged (multivariable HR for death without LTx, 1.56 [95%CI, 1.32-1.84]; multivariable HR for LTx, 0.47 [95%CI, 0.36-0.62]). There are lower rates of LTx and an increased risk of death without LTx for US patients with CF with FEV1< 40%predicted compared with Canadian patients. Findings are more striking among US patients with CF with Medicaid/Medicare health insurance, and nonwhite patients in both countries, raising concerns about underuse of LTx among vulnerable populations.

Cystic Fibrosis Point of Personalized Detection (CFPOPD): An Interactive Web Application.

BackgroundDespite steady gains in life expectancy, individuals with cystic fibrosis (CF) lung disease still experience rapid pulmonary decline throughout their clinical course, which can ultimately end in respiratory failure. Point-of-care tools for accurate and timely information regarding the risk of rapid decline is essential for clinical decision support.ObjectiveThis study aims to translate a novel algorithm for earlier, more accurate prediction of rapid lung function decline in patients with CF into an interactive web-based application that can be integrated within electronic health record systems, via collaborative development with clinicians.MethodsLongitudinal clinical history, lung function measurements, and time-invariant characteristics were obtained for 30,879 patients with CF who were followed in the US Cystic Fibrosis Foundation Patient Registry (2003-2015). We iteratively developed the application using the R Shiny framework and by conducting a qualitative study with care provider focus groups (N=17).ResultsA clinical conceptual model and 4 themes were identified through coded feedback from application users: (1) ambiguity in rapid decline, (2) clinical utility, (3) clinical significance, and (4) specific suggested revisions. These themes were used to revise our application to the currently released version, available online for exploration. This study has advanced the application’s potential prognostic utility for monitoring individuals with CF lung disease. Further application development will incorporate additional clinical characteristics requested by the users and also a more modular layout that can be useful for care provider and family interactions.ConclusionsOur framework for creating an interactive and visual analytics platform enables generalized development of applications to synthesize, model, and translate electronic health data, thereby enhancing clinical decision support and improving care and health outcomes for chronic diseases and disorders. A prospective implementation study is necessary to evaluate this tool’s effectiveness regarding increased communication, enhanced shared decision-making, and improved clinical outcomes for patients with CF.

What effective ways of motivation, support and technologies help people with cystic fibrosis improve and sustain adherence to treatment?

Introduction“What effective ways of motivation, support and technologies help people with cystic fibrosis improve and sustain adherence to treatment?” was identified as one of the James Lind Alliance Priority Setting...