Treatment of small as well as large declines in lung function enhances recovery to baseline in people with CF.

BACKGROUND: The benefit of antibiotic treatment of acute drops in FEV1 percent predicted (FEV1pp) has been clearly established, but data from the early 2000s showed inconsistent treatment. Further, there is no empirical evidence for what magnitude of drop is clinically significant. METHODS: We used data from the CF Foundation Patient Registry (CFFPR) from 2016 to 2019 to determine the association between treatment (any IV antibiotics, only oral or newly prescribed inhaled antibiotics, or no antibiotic therapy) following a decline of ≥5% from baseline FEV1pp and return to 100% baseline FEV1pp days using multivariable logistic regression including an interaction between the magnitude of decline and treatment category. RESULTS: Overall, 16,495 PWCF had a decline: 16.5% were treated with IV antibiotics, 25.0% non-IV antibiotics, and 58.5% received no antibiotics. Antibiotic treatment was more likely for those with lower lung function, history of a positive PA culture, older age and larger FEV1 decline (p < 0.001). Treatment with IV antibiotics or oral/inhaled antibiotics was associated with a higher odds of recovery to baseline compared to no treatment across all levels of decline, including declines of 5%-10%. CONCLUSIONS: A large proportion of acute drops in FEV1pp continue to be untreated, especially in younger patients and those with higher baseline lung function. Acute drops as small as 5% predicted are less likely to be recovered if antibiotic treatment is not prescribed. These findings suggest the need for more aggressive antimicrobial treatment of acute drops in FEV1, including those of a magnitude previously believed to be associated with self-recovery.

Clinical outcomes at 9-10 years of age in children born with cystic fibrosis transmembrane conductance regulator related metabolic syndrome.

BACKGROUND AND OBJECTIVES: There are limited data on cystic fibrosis (CF) transmembrane conductance regulator-related metabolic syndrome (CRMS) outcomes beyond infancy. The goal of this study was to analyze outcomes of infants with CRMS up to the age of 9-10 years using the CF Foundation Patient Registry (CFFPR). METHODS: We analyzed data from the CFFPR for individuals with CF and CRMS born between 2010 and 2020. We classified all patients based on the clinical diagnosis reported by the CF care center and the diagnosis using CFF guideline definitions for CF and CRMS, classifying children into groups based on agreement between clinical report and guideline criteria. Descriptive statistics for the cohort were calculated for demographics, nutritional outcomes, and microbiology for the first year of life and lung function and growth outcomes were summarized for ages 6-10 years. RESULTS: From 2010 to 2020, there were 8765 children with diagnosis of CF or CRMS entered into the CFFPR with sufficient diagnostic data for classification, of which 7591 children had a clinical diagnosis of CF and 1174 had a clinical diagnosis of CRMS. CRMS patients exhibited normal nutritional indices and pulmonary function up to age 9-10 years. The presence of respiratory bacteria associated with CF, such as Pseudomonas aeruginosa from CRMS patients ranged from 2.1% to 9.1% after the first year of life. CONCLUSIONS: Children with CRMS demonstrate normal pulmonary and nutritional outcomes into school age. However, a small percentage of children continue to culture CF-associated respiratory pathogens after infancy.

Impact of loss to follow-up on survival estimation for cystic fibrosis.

PURPOSE: Deaths among those lost to follow-up (LTFU) in the Cystic Fibrosis Foundation Patient Registry (CFFPR) are critically important to the epidemiology of cystic fibrosis (CF). Unreported deaths could impact estimates of survival if LTFU is associated with disease trajectory. METHODS: We characterized the LTFU population (1986-2017) from the CFFPR and identified deaths via linkage with the National Death Index (NDI). Median predicted survival age and conditional survival were estimated with and without additional deaths and person-time from the NDI. RESULTS: Of the 10,582 individuals LTFU in the CFFPR, 2,460 (23.2%) matched to an NDI death record. Individuals who died after LTFU with a CF diagnosis were 43% female, 91% White/non-Hispanic, 59% had advanced CF lung disease based on last CFFPR recorded forced expiratory volume in one second (FEV1) %predicted <40 and 18% were post-lung transplant. Median predicted survival age during the most recent period available, 2013-2017, increased from 44.3 years (95% CI: 43.2, 45.7) to 45.8 years (95% CI 44.5, 47.1) with the inclusion of NDI data. CONCLUSIONS: Inclusion of deaths and additional person-time among those LTFU changed the point estimate of median predicted survival for most time periods and increased the point estimate from 2009 onwards.

Lung Function Decline in Cystic Fibrosis: Impact of Data Availability and Modeling Strategies on Clinical Interpretations.

Rationale: Studies estimating the rate of lung function decline in cystic fibrosis have been inconsistent regarding the methods used. How the methodology used impacts the validity of the results and comparability between studies is unknown. Objectives: The Cystic Fibrosis Foundation established a work group whose tasks were to examine the impact of differing approaches to estimating the rate of decline in lung function and to provide analysis guidelines. Methods: We used a natural history cohort of 35,252 individuals with cystic fibrosis aged ⩾6 years in the Cystic Fibrosis Foundation Patient Registry (CFFPR), 2003-2016. Modeling strategies using linear and nonlinear forms of marginal and mixed-effects models, which have previously quantified the rate of forced expiratory volume in 1 second (FEV1) decline (percent predicted per year), were evaluated under clinically relevant scenarios of available lung function data. Scenarios varied by sample size (overall CFFPR, medium-sized cohort of 3,000 subjects, and small-sized cohort of 150), data collection/reporting frequency (encounter, quarterly, and annual), inclusion of FEV1 during pulmonary exacerbation, and follow-up length (<2 yr, 2-5 yr, entire duration). Results: Rate of FEV1 decline estimates (percent predicted per year) differed between linear marginal and mixed-effects models; overall cohort estimates (95% confidence interval) were 1.26 (1.24-1.29) and 1.40 (1.38-1.42), respectively. Marginal models consistently estimated less rapid lung function decline than mixed-effects models across scenarios, except for short-term follow-up (both were ∼1.4). Rate of decline estimates from nonlinear models diverged by age 30. Among mixed-effects models, nonlinear and stochastic terms fit best, except for short-term follow-up (<2 yr). Overall CFFPR analysis from a joint longitudinal-survival model implied that an increase in rate of decline of 1% predicted per year in FEV1 was associated with a 1.52-fold (52%) increase in the hazard of death/lung transplant, but the results exhibited immortal cohort bias. Conclusions: Differences were as high as 0.5% predicted per year between rate of decline estimates, but we found estimates were robust to lung function data availability scenarios, except short-term follow-up and older age ranges. Inconsistencies among previous study results may be attributable to inherent differences in study design, inclusion criteria, or covariate adjustment. Results-based decision points reported herein will support researchers in selecting a strategy to model lung function decline most reflective of nuanced, study-specific goals.

Real-world Associations of US Cystic Fibrosis Newborn Screening Programs With Nutritional and Pulmonary Outcomes.

Importance: Newborn screening (NBS) for cystic fibrosis (CF) has been universal in the US since 2010, but its association with clinical outcomes is unclear. Objective: To describe the real-world effectiveness of NBS programs for CF in the US on outcomes up to age 10 years. Design, Setting, and Participants: This was a retrospective cohort study using CF Foundation Patient Registry data from January 1, 2000, to December 31, 2018. The staggered implementation of NBS programs by state was used to compare longitudinal outcomes among children in the same birth cohort born before vs after the implementation of NBS for CF in their state of birth. Participants included children with an established diagnosis of CF born between January 1, 2000, to December 31, 2018, in any of the 44 states that implemented NBS for CF between 2003 and 2010. Data were analyzed from October 5, 2020, to April 22, 2022. Exposures: Birth before vs after the implementation of NBS for CF in the state of birth. Main Outcomes and Measures: Longitudinal trajectory of height and weight percentiles from diagnosis, lung function (forced expiratory volume in 1 second, [FEV1] percent predicted) from age 6 years, and age at initial and chronic infection with Pseudomonas aeruginosa using linear mixed-effects and time-to-event models adjusting for birth cohort and potential confounders. Results: A total of 9571 participants (4713 female participants [49.2%]) were eligible for inclusion, with 4510 (47.1%) in the pre-NBS cohort. NBS was associated with higher weight and height percentiles in the first year of life (weight, 6.0; 95% CI, 3.1-8.4; height, 6.6; 95% CI, 3.8-9.3), but these differences decreased with age. There was no association between NBS and FEV1 at age 6 years, but the percent-predicted FEV1 did increase more rapidly with age in the post-NBS cohort. NBS was associated with older age at chronic P aeruginosa infection (hazard ratio, 0.69; 95% CI, 0.54-0.89) but not initial P aeruginosa infection (hazard ratio, 0.88; 95% CI, 0.77-1.01). Conclusions and Relevance: NBS for CF in the US was associated with improved nutritional status up to age 10 years, a more rapid increase in lung function, and delayed chronic P aeruginosa infection. In the future, as highly effective modulator therapies become available for infants with CF, NBS will allow for presymptomatic initiation of these disease-modifying therapies before irreversible organ damage.

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.

Bone mineral density screening by DXA for people with cystic fibrosis: A registry analysis of patient and program factors influencing rates of screening.

BACKGROUND: Current guidelines recommend screening for Cystic Fibrosis (CF) related bone disease (CFBD) using dual-energy x-ray absorptiometry (DXA) for all people ≥ 18 years of age and select people ≥ 8 years of age. However, adherence to these guidelines is variable. This study aims to evaluate screening practices among adult programs in the US and identify patient and program-based characteristics which may influence screening. METHODS: The CF Foundation Patient Registry (CFFPR) was used to identify all people over the age of 18 who were seen at adult CF programs and received screening for CFBD using DXA at least once between 2014 and 2018. Associations with patient and program level characteristics were assessed using the Chi Square test. Patient level variables were also examined using standardized difference to assess for meaningful clinical differences in rates of screening. RESULTS: From 2014 to 2018, a total of 15,134 people over the age of 18 were identified in the CFFPR. Of these people, 9,023 (60%) received a DXA during the time period. The median rate of screening by program was 66% and programs in the highest quartile of screening obtained DXAs on >76% of their population. At the program level, larger size and increased adherence to other guideline practices such as OGTT screening and 4 visits, 4 cultures in a year correlated with higher rates of screening for CFBD. At the patient-level, people with lower lung function (FEV1 <90%) and those with CF related diabetes were more likely to be screened. People without health insurance were less likely to receive recommended screening. CONCLUSION: Screening practices for CFBD vary widely across adult programs in the US despite recommendations to screen all people over the age of 18. Factors identified in this analysis may be used to identify those people at highest risk of missing appropriate screening. CFBD has significant implications for our patients and therefore routine screening should be emphasized as part of standard care moving forward.

Lung function in children with cystic fibrosis in the USA and UK: a comparative longitudinal analysis of national registry data.

RATIONALE: A 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. OBJECTIVES: To compare longitudinal trajectories of lung function in children with CF between the USA and UK and to explore reasons for any differences. METHODS: We 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). RESULTS: We 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. CONCLUSIONS: Children 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.

Prevalence, variability, and predictors of sinus surgery in pediatric patients with cystic fibrosis.

INTRODUCTION: Chronic rhinosinusitis is common among individuals with cystic fibrosis (CF) and has an impact on quality of life. Sinus surgery is a treatment option, but minimal literature exists regarding prevalence and indications. METHODS: Using the linked CF Foundation Patient Registry (CFFPR) - Pediatric Health Information Systems (PHIS) database, we investigated variability in receipt of surgery, predictors of surgery, and time to first surgery. We included individuals less than 18 receiving care between 2006 and 2015 at a CF Foundation care program that is also a PHIS-participating-hospital. We used logistic regression to examine predictors of receipt of surgery and a Kaplan-Meier curve to examine time to first surgery among those born 2005-2007. RESULTS: There were 11,545 children and adolescents and 2156 (18.7%) received at least one surgery. Variation in number of surgeries was observed across hospitals (median: 63 [IQR, 33-110]). There was an inconsistent pattern between receipt of surgery and markers of disease severity; those receiving surgery having increased odds of treatment use and pulmonary exacerbations and decreased odds of lower lung function and body mass index. Among the cohort of young children, 159 (14%) had at least one surgery with a median age at first surgery of 5.6 (IQR, 3.9-7.0). CONCLUSIONS: The use of sinus surgery is frequent, but variable, among children and adolescents. Clinical factors are associated with receipt of surgery, but further understanding is needed on other factors that impact variability in use. Our study indicates the need for additional evaluation of the management of CF-related CRS and indications for surgery.

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.

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 < 40% predicted? 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 < 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. RESULTS: 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]). INTERPRETATION: 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.

Bridging the survival gap in cystic fibrosis: An investigation of lung transplant outcomes in Canada and the United States.

BACKGROUND: 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. METHODS: 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. RESULTS: 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 (p < 0.01) 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. CONCLUSIONS: Differences in waitlist mortality and post-transplant survival can explain up to a third of the survival gap observed between the US and Canada.

Decreased survival in cystic fibrosis patients with a positive screen for depression.

BACKGROUND: The International Depression Epidemiological Study (TIDES) found elevated rates of screen positivity for depression and anxiety among individuals with cystic fibrosis (CF). Depression is associated with worse adherence and health-related quality of life in CF. We investigated the relationship with mortality. METHODS: Subjects were untransplanted participants in TIDES 12+ years of age receiving care at one of 45 collaborating US CF care centers who completed the Hospital Anxiety and Depression Scale and/or Center for Epidemiologic Studies Depression Scale during a stable visit between 2006 and 2010. Clinical characteristics and mortality data were obtained from the CF Foundation Patient Registry. The association of a positive screen with 5-year survival was evaluated using Cox Proportional Hazards modeling. RESULTS: Of 1005 eligible patients, 25% screened positive for depression and 34% screened positive for anxiety. Patients who screened positive for depression were more likely to be older, have a residual function mutation, public insurance, and more pulmonary exacerbations in the screening year. There were 96 deaths. The unadjusted 5-year Hazard Ratio (HR) for death among those with depression was 2.0; 95% CI (1.3, 3.0)]. When adjusted for predetermined potential confounders the HR for the entire population was 1.4; 95% CI (0.9, 2.2). The adjusted HR was higher in adults [1.6; 95% CI (1.0, 2.4)] and those screening in the severe range [2.0; 95% CI (1.2, 3.4)]. Anxiety was not associated with mortality. CONCLUSIONS: A positive depression screen is associated with increased mortality among adults with CF. Research into the etiology of this relationship is needed.

Impact of Socioeconomic Position on Access to the U.S. Lung Transplant Waiting List in a Matched Cystic Fibrosis Cohort.

Rationale: Referrals for lung transplant and transplant rates in the United States are lower than in Canada for patients with advanced cystic fibrosis (CF) lung disease. Further study of factors limiting access are needed to optimize referral and transplant for this population.Objectives: To determine the effect of socioeconomic position, while accounting for disease severity, on the likelihood of wait-listing for lung transplant in the United States.Methods: A case-control study of 3,110 patients (1,555 wait-listed, 1,555 never wait-listed) in the linked CF Foundation Patient Registry/Scientific Registry of Transplant Recipients was performed with 1:1 matching for age, forced expiratory volume in 1 second, and year. Logistic regression was performed with univariate and multivariate analyses accounting for eight clinical factors (sex, oxygen use, body mass index, hemoptysis, forced vital capacity, methicillin-resistant Staphylococcus aureus, multidrug-resistant Pseudomonas aeruginosa, and i.v. antibiotic days) and six socioeconomic factors (race, marital status, education, health insurance, median zip code income, and distance to transplant program). The CF Health Score and Socioeconomic Barrier Score were created based on summation of variables. Interactions between scores were calculated.Results: We found an inverse relationship between the probability of wait-listing and CF Health Score and Socioeconomic Barrier Score. As the CF Health Score decreased (less healthy), the probability of wait-listing increased by 69.3% from a score of 7 to 2. As the Socioeconomic Barrier Score decreased (fewer barriers), the probability of wait-listing increased by 31.7% from a score of ≥5 to 1). Regardless of illness severity, socioeconomic barriers presented an impediment to wait-listing. Individuals with higher Socioeconomic Barrier Scores accessed transplant about half as often as those with lower scores at the same level of medical severity. Analysis of interactions demonstrated a higher probability of wait-listing for individuals with moderate health severity and fewer social barriers compared with sicker individuals with more socioeconomic barriers.Conclusions: Accrual of socioeconomic barriers limits access to lung transplant irrespective of disease severity, a finding of substantial concern for patients with CF and for transplant providers. Future interventions can focus on this at-risk population early in the disease course.

Predictors of pulmonary exacerbation treatment in cystic fibrosis.

BACKGROUND: Most studies of pulmonary exacerbations (PEx) in cystic fibrosis (CF) focus on intravenous (IV)-treated PEx, though most PEx are treated with oral antibiotics. Our objectives were to describe predictors of antibiotic choice and outcomes for PEx initially identified in clinic. METHODS: For each patient in the U.S. CF Foundation Patient Registry, we selected the first PEx recorded at a clinic visit in 2013-14 following a clinic visit without a PEx. We used multivariable logistic regression to determine associations between clinical characteristics and antibiotic treatment choice. We determined outcomes in the 90 days after the first PEx. RESULTS: Among 14,265 patients with a PEx initially identified in clinic, 21.4% received no antibiotics, 61.5% received new oral and/or inhaled antibiotics, and 17.0% had IV antibiotics within 14 days. Compared to IV antibiotics, patients more likely to receive new oral and/or inhaled antibiotics: were male, <13 years old, had BMI >10th percentile or 18.5 kg/m2, >90 days between clinic visits, FEV1 > 70% predicted at the PEx, no prior-year IV-treated PEx, FEV1 decline <10% predicted, and private insurance. Following the PEx, 30.3% of patients had no clinical encounters within 90 days. Treatment with IV antibiotics within 90 days occurred for 23.7% treated without antibiotics, 22.8% of new oral and/or inhaled antibiotics, and 27.1% of IV antibiotics. CONCLUSION: Most PEx identified in clinic are treated with new oral and/or inhaled antibiotics. Markers of disease severity are associated with antibiotic treatment choice. Many patients had no follow-up evaluation within 90 days of treatment.

Rapid lung function decline in adults with early-stage cystic fibrosis lung disease.

RATIONALE: The prevalence of adults living with cystic fibrosis (CF) who have early-stage lung disease is increasing. OBJECTIVES: Describe the prevalence and evaluate spirometric risk factors associated with the subgroup of patients with early-stage lung disease and FEV1 decline of ≥5% predicted/year. METHODS: Retrospective cohort study of patients ≥18 years with FEV1% predicted ≥80% included in the US CF Foundation Patient Registry from 2010-2013. Regression models were developed to estimate FEV1 rate of decline. Multivariable logistic analysis was used to assess if spirometric risk factors were associated with FEV1 decline. MEASUREMENTS AND MAIN RESULTS: 3,029 subjects were in the study cohort. Approximately 15% of the cohort had a substantial decline in lung function ≥5% predicted/year. In multivariable models adjusted for confounders, FEV1/FVC ratio <0.8 (Odds Ratio (OR) 1.63, 95% confidence interval (CI) 1.31 to 2.02) and history of FEV1% predicted variability (OR 2.35,95%CI 1.74 to 3.18) were associated with rapid lung function decline. CONCLUSIONS: Even among adults with early-stage lung disease, approximately 15% are shown to progress and experience a large decline in lung function. This reinforces the concept that lung function in early-stage CF is not normal or mild. Rather, lung function decline may be delayed, but not avoided, in these individuals. Variability in FEV1% predicted and airway obstruction as measured by FEV1/FVC ratio may identify individuals at increased risk of decline. Adults with early-stage lung disease should be followed in clinic to monitor for onset of decline.

Palivizumab and Long-term Outcomes in Cystic Fibrosis.

BACKGROUND: The American Academy of Pediatrics does not recommend routine use of palivizumab prophylaxis for infants with cystic fibrosis (CF) but recommends consideration in infants with clinical evidence of chronic lung disease or nutritional compromise. However, the beneficial impact of palivizumab on longer-term outcomes is uncertain. METHODS: We used Cystic Fibrosis Foundation Patient Registry data to assess the association of receiving palivizumab during the first 2 years of life with longer-term outcomes, including lung function at 7 years old, time to first positive Pseudomonas respiratory culture, and pulmonary-related hospitalizations during the first 7 years of life. Eligible infants were born from 2008 to 2015 and diagnosed with CF during the first 6 months of life. Demographic and clinical confounders of association between palivizumab receipt and outcomes were explored. We created propensity scores to adjust for potential confounding by indication (ie, sicker infants were more likely to receive palivizumab). For each outcome, we performed regression analyses adjusted by propensity scores. RESULTS: The sample included 4267 infants; 1588 (37%) received palivizumab. Mean percent forced expiratory volume in 1 second predicted at 7 years old was similar among those who did (98.2; 95% confidence interval: 96.9-99.5) and did not (97.3; 95% confidence interval: 96.1-98.5) received palivizumab, adjusting for propensity scores. Time to first positive Pseudomonas aeruginosa culture and annual risk of hospitalization were similar among those who did and did not receive palivizumab. CONCLUSIONS: At the population level, palivizumab receipt was not associated with improved longer-term outcomes in children with CF.

Effect of Including Important Clinical Variables on Accuracy of the Lung Allocation Score for Cystic Fibrosis and Chronic Obstructive Pulmonary Disease.

Rationale: Clinical variables associated with shortened survival in patients with advanced-stage cystic fibrosis (CF) are not included in the lung allocation score (LAS).Objectives: To identify variables associated with wait-list and post-transplant mortality for CF lung transplant candidates using a novel database and to analyze the impact of including new CF-specific variables in the LAS system.Methods: A deterministic matching algorithm identified patients from the Scientific Registry of Transplant Recipients and the Cystic Fibrosis Foundation Patient Registry. LAS wait-list and post-transplant survival models were recalculated using CF-specific variables. This multicenter, retrospective, population-based study of all lung transplant wait-list candidates aged 12 years or older from January 1, 2011, to December 31, 2014, included 9,043 patients on the lung transplant waiting list and 6,110 lung transplant recipients between 2011 and 2014, comprising 1,020 and 677 with CF, respectively.Measurements and Main Results: Measured outcomes were changes in LAS and lung allocation rank. For CF candidates, any Burkholderia sp. (hazard ratio [HR], 2.8; 95% confidence interval [CI], 1.2-6.6), 29-42 days hospitalized (HR 2.8; CI 1.3-5.9), massive hemoptysis (HR 2.1; CI 1.1-3.9), and relative drop in FEV1 ≥30% over 12 months (HR 1.7; CI 1.0-2.8) increased wait-list mortality risk; pulmonary exacerbation time 15-28 days (1.8; 1.1-2.9) increased post-transplant mortality risk. A relative drop in FEV1 ≥10% in chronic obstructive pulmonary disease (COPD) candidates was associated with increased wait-list mortality risk (HR 2.6; CI 1.2-5.4). Variability in LAS score and rank increased in patients with CF. Priority for transplant increased for COPD candidates. Access did not change for other diagnosis groups.Conclusions: Adding CF-specific variables improved discrimination among wait-listed CF candidates and benefited COPD candidates.

Linkage of the CF foundation patient registry with the pediatric health information system database.

INTRODUCTION: The Cystic Fibrosis Foundation Patient Registry (CFFPR) contains clinical and demographic data from ∼85% of US cystic fibrosis (CF) patients across 120 care centers, but lacks robust inpatient hospitalization data. In contrast, the Pediatric Health Information System (PHIS) database includes inpatient clinical and resource utilization data from 49 US children's hospitals. The creation of a linked CFFPR-PHIS dataset can uniquely address questions related to in-hospital pediatric CF treatment and management. We assessed the feasibility of linking the CFFPR and PHIS databases and determined if successfully linked CF patients were generalizable to unlinked patients. METHODS: CF patients ≤21 years were eligible for linkage. The CFFPR and PHIS databases were linked at the patient level using indirect identifiers in a stepwise, deterministic, linkage approach. A validation cohort was created using a subset of patients to determine linkage accuracy. Clinical and demographic characteristics between linked and unlinked patients were compared to determine generalizability of the linked cohort. RESULTS: Of the 11 735 CF patients eligible for linkage from January 1st, 2005 through December 31st, 2016, 10 660 (91%) were successfully linked. Results of our single center validation cohort illustrated 100% accuracy. When compared to unlinked CF patients, fewer linked patients were born before 1990, more were Hispanic, and more were from West-affiliated PHIS hospitals. Otherwise, no clinically meaningful differences were seen between linked and unlinked CF patients. CONCLUSIONS: We demonstrated successful linkage of the CFFPR and PHIS databases, and created a large generalizable pediatric CF cohort for use in CF-related research.

Rate and predictors of prescription of lumacaftor - Ivacaftor in the 18 months following approval in the United States.

RATIONALE: Lumacaftor-ivacaftor (LUM-IVA) was approved in the US in 2015 for patients with CF aged >12 homozygous for the delF508 mutation, and patients aged 6 to 12 in 2016. OBJECTIVES: To examine the rate of initial LUM-IVA prescriptions following approval. METHODS: We compared patients eligible for LUM-IVA in the CF Foundation Patient Registry with and without prescriptions in 2015-2016. RESULTS: 5534 (53%) eligible patients had reported prescriptions. Prescription rate in children ages 6-11 was 19% and 61% among patients ≥12 years old. Individuals ≥12 with prescriptions more likely observed among those with private insurance, clinical trial participation, ages 18-30, FEV1 < 90%, more pulmonary exacerbations, and more use of chronic medications. CONCLUSIONS: LUM-IVA uptake was less rapid than what was previously observed for ivacaftor, a CFTR modulator approved for a different population. Age, insurance status, disease severity and use of other therapies differed in those prescribed LUM-IVA in the initial post-approval period.