Lung function decline is mitigated following liver transplantation in people with cystic fibrosis: A retrospective cohort study.

There is paucity of literature on the health outcomes following liver transplantation (LT) in people with cystic fibrosis (pwCF). We aim to evaluate changes in lung function following LT in pwCF. We performed a retrospective cohort study of pwCF who underwent LT between 1987 and 2019 in the United States and Canada. Simultaneous lung-liver transplants and individuals who had lung transplant prior to LT were excluded. We analyzed pre-LT and post-LT percent predicted forced expiratory volume in 1 second, body mass index, rates of pulmonary exacerbation, and post-LT overall survival. A total of 402 LT recipients were included. The median age of transplant was 14.9 years and 69.7% of the transplants were performed in children less than 18 years old. The rate of decline in percent predicted forced expiratory volume in 1 second was attenuated after LT from -2.2% to -0.7% predicted per year with a difference of 1.5% predicted per year (95% CI, 0.8, 2.2; p < 0.001). Following LT, the rate of decline in body mass index was reduced, and there were fewer pulmonary exacerbations (0.6 pre vs. 0.4 post; rate ratio 0.7, p < 0.01). The median survival time post-transplant was 13.9 years and the overall probability of survival at 5 years was 77.6%. Those with higher lung function pre-LT had a lower risk of death post-LT, and those with genotypes other than F508 deletion had worse survival. LT in pwCF occurs most often in children and adolescents and is associated with a slower rate of decline in lung function and nutritional status, and a reduction in pulmonary exacerbations.

Late Diagnosis in the Era of Universal Newborn Screening Negatively Affects Short- and Long-Term Growth and Health Outcomes in Infants with Cystic Fibrosis.

Newborn screening for cystic fibrosis was fully implemented in the US by 2010, but delays in timeliness of evaluation for infants with positive newborn screening tests persist. Through evaluation of national patient registry data, we determined that late initiation of cystic fibrosis care is associated with poorer long-term nutritional outcomes.

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

INTRODUCTION: 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). METHODS: 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. RESULTS: 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%). CONCLUSIONS: 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.

Comparison of Nutrition and Lung Function Outcomes in Patients with Cystic Fibrosis Living in Canada and the United States.

RATIONALE: 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. OBJECTIVES: 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. METHODS: 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. MEASUREMENTS AND MAIN RESULTS: We conducted three analyses: survival differences by birth cohort; population trends for FEV1 and body mass index (BMI) over time; and individual patient FEV1 and BMI trajectories. The study included a total of 37,772 patients in the United States and 5,149 patients in Canada. Patients with CF experienced significant improvements in nutritional status and lung function in both Canada and the United States during the study. In addition, the survival gap between the two countries is narrowing within younger birth cohorts. The improvements for the patients within the United States were most prominent in the BMI trajectories, where patients born after 1990 in the United States have higher BMI that has persisted over time. CONCLUSIONS: The 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.

Data from the US and UK cystic fibrosis registries support disease modification by CFTR modulation with ivacaftor.

BACKGROUND: Ivacaftor 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. OBJECTIVE: This 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. METHODS: Annual 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. RESULTS: Analyses 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%, p<0.0001) and pulmonary exacerbation (27.8% vs 43.3%, p<0.0001) relative to comparators; trends were similar in the UK. In both registries, ivacaftor-treated patients had a lower prevalence of CF-related complications and select microorganisms and had better preserved lung function. CONCLUSIONS: While 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 NUMBER: EUPAS4270.

Clinical characteristics of cystic fibrosis patients prior to lung transplantation: An international comparison between Canada and the United States.

BACKGROUND: Cystic fibrosis (CF) patients from Canada have better-reported post-lung transplant survival compared to patients from the United States. We hypothesized the clinical characteristics of CF patients prior to lung transplant differ between the two countries. METHODS: Population-based cohort study utilizing combined Canadian CF Registry and US CF Foundation Patient Registry data from 1986 to 2013. Demographic and clinical variables were analyzed prior to lung transplant. RESULTS: Between 1986 and 2013, 607 (10.2%) CF patients underwent lung transplantation in Canada and 3428 (7.5%) in the United States. A lower proportion of recipients had growth of B. cepacia complex prior to transplant in the United States compared to Canada (0.8% vs 4.3%). Lung function was similar between recipients from the two countries. The proportion of patients classified as underweight was significantly higher in the United States compared to Canada (39.8% vs 28.0%; SD 26.1) despite higher rates of feeding tube use (42.5% vs 28.6%; SD 29.0). CONCLUSIONS: CF lung transplant recipients from the United States have similar lung function, lower rates of B. cepacia complex, and worse nutritional parameters prior to transplant compared to counterparts in Canada. Future studies are necessary to evaluate the impact of these differences on post-transplant survival.

Survival Comparison of Patients With Cystic Fibrosis in Canada and the United States: A Population-Based Cohort Study.

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.

Children and young adults with CF in the USA have better lung function compared with the UK.

BACKGROUND: People with cystic fibrosis (CF) are managed differently in the USA and UK providing an opportunity to learn from differences in practice patterns. OBJECTIVES: To compare cross-sectional demographics, practice patterns and clinical outcomes between US and UK CF patients. METHODS: This was a cross-sectional study using 2010 data from patients in the US Cystic Fibrosis Foundation and the UK Cystic Fibrosis patient registries. The a priori outcome measures of interest were lung function and nutritional status. Descriptive statistics and two sample comparisons were performed. Stratification and multivariable linear regression were used to adjust for confounding. RESULTS: The study cohort included 13 777 children and 11 058 adults from the USA and 3968 children and 3965 adults from the UK. In children, mean body mass index centiles were similar. Lung function (FEV1 and FVC% predicted) was significantly higher in US patients ages 6-25 years of age. In a regression model adjusted for only age, FEV1% predicted was on average 3.31% of predicted (95% CI 2.65 to 3.96) higher in the USA compared with the UK. When adjusted for age, age at diagnosis, gender, pancreatic insufficiency and genotype, FEV1% predicted was on average 3.03% of predicted (95% CI 2.37 to 3.69) higher in the USA compared with the UK These differences persisted despite adjustment for possible confounders. Hypertonic saline and dornase alfa were much more commonly prescribed in US children. CONCLUSIONS: Children and young adults with CF have better lung function in the USA compared with the UK despite similar nutritional status.

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

BACKGROUND: Ivacaftor 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 CF and an R117H variant on ivacaftor using data from the US Cystic Fibrosis Foundation Patient Registry. METHODS: Key outcomes were evaluated in ivacaftor-treated people with CF and an R117H variant for up to 36 months before and after treatment initiation using within-group comparisons. Analyses were descriptive in nature, focused on evaluation of observed outcome patterns over time and were performed both overall and for age groups ≥2 to <6 years, ≥6 to <18 years and ≥18 years. Key outcomes included lung function, body mass index (BMI), pulmonary exacerbations (PEx) and hospitalisations. RESULTS: The ivacaftor cohort included 369 people with CF and an R117H variant who initiated therapy between 1 January 2015 and 31 December 2016. During each of the 12-month intervals following treatment initiation, the mean observed percent predicted forced expiratory volume in 1 s (ppFEV1) and BMI values were higher and the mean annualised number of PEx and hospitalisation events were lower than pretreatment values. Mean change in ppFEV1 from pretreatment baseline was an increase of 1.5 (95% CI 0.8 to 2.3), 1.7 (95% CI 0.7 to 2.7) and 1.8 (95% CI 0.6 to 3.0) percentage points in the first, second and third years of treatment, respectively. Similar trends were observed in adult and paediatric subgroups. CONCLUSIONS: The results support the clinical effectiveness of ivacaftor in people with CF and an R117H variant, including adult and paediatric subgroups.

Disparities in first evaluation of infants with cystic fibrosis since implementation of newborn screening.

OBJECTIVE: We evaluated whether implementation of cystic fibrosis (CF) newborn screening (NBS) leads to equitable timeliness of initial evaluation. We compared age at first event (AFE, age at sweat test, encounter and/or care episode) between infants categorized as Black/African American, American Indian/ Native Alaskan, Asian, and/or Hispanic and/or other (Group 1) to White and not Hispanic infants (Group 2). METHODS: This retrospective cohort study from the Cystic Fibrosis Foundation Patient Registry (CFFPR) included infants born 2010-2018. Race and ethnicity categories followed US Census definitions. The primary outcome was AFE; the secondary outcome was weight for age (WFA) z-score averaged 12 to < 24 months. We compared distributions by Wilcoxon rank-sum test and proportions by Chi-square or Fisher's exact tests. A nested cohort study used a linear mixed effects model of variables that affect WFA, chosen a priori, to evaluate associations with 1-year WFA z-score. RESULTS: Among 6354 infants, 21% were in Group 1. Group 1 median AFE was 31 days (IQR 19, 49) and Group 2 was 22 days (IQR 14,36) (p< .001). Median WFA z-score at 1-2 years was lower in Group 1. In 3017 infants with complete data on variables of interest, AFE, Black race, CFTR variant class I-III, prematurity and public insurance were associated with lower 1-year WFA z-score. CONCLUSIONS: Differences in AFE for infants with CF from historically marginalized groups may exacerbate long standing health disparities. We speculate that inequitable identification of CFTR gene variants and/or bias may influence timeliness of evaluation after an out-of-range NBS.

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

BACKGROUND: Phase 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. METHODS: The 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. RESULTS: 16,116 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). CONCLUSIONS: ELX/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.

Cystic fibrosis prevalence in the United States and participation in the Cystic Fibrosis Foundation Patient Registry in 2020.

BACKGROUND: The Cystic Fibrosis Foundation Patient Registry (CFFPR) collects data on individuals with cystic fibrosis (CF) in the United States (US). In 2012, the US CF population was estimated at 33,292 to 34,327 individuals, with 81-84% CFFPR participation. METHODS: In this study, we update these estimates via simulation to account for uncertainty in CF incidence by race or Hispanic ethnicity, initiation of CF newborn screening (NBS) programs by state, and updated cumulative survival for CF births 1968-2020. We defined registry participation as the proportion of individuals alive as of 2020 with any prior CFFPR participation as well as the proportion with contributing data in 2019 or 2020; we summarize CFFPR participation for those born prior to 1968. RESULTS: We estimated the 2020 prevalent CF population between 1968-2020 to be 38,804 (95% Uncertainty Interval (UI): 38,532 to 39,065) individuals, with 77% of the prevalent CF population contributing recent data. CFFPR participation differs by age (54% of those born in 1968) and exceeds >90% of the population born in 2009 or later. CONCLUSIONS: We demonstrate that the CFFPR remains a valid data source generalizable to the CF population. High participation among younger individuals may reflect the success of newborn screening programs and early referral to CF care. If engagement can be sustained, the percentage of individuals participating in the CFFPR will grow over time and there is an opportunity to identify factors associated with loss to follow up among older individuals to optimize the quality of the CFFPR data.

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.

Changes in Care during the COVID-19 Pandemic for People with Cystic Fibrosis.

Rationale: Cystic fibrosis (CF) centers transitioned to telemedicine during the spring 2020 peak of the coronavirus disease (COVID-19) pandemic. Objectives: We hypothesized that people with CF (pwCF) with more severe disease would be more likely to be seen in-person. Methods: We used paired t tests to compare within-subject changes in body mass index (BMI) and percentage predicted forced expiratory volume in one second (FEV1) and calculated relative risk (RR) to compare pulmonary exacerbations (PEx) between pwCF enrolled in the CF Foundation Patient Registry with at least one in-person clinic visit after March 15 in both 2019 and 2020. Results: Overall, the proportion of clinical encounters that were in-person clinic visits decreased from 91% in 2019 to a low of 9% in April 2020. Among pwCF seen after March 15 in both 2019 and 2020, the mean (95% confidence interval [CI]) FEV1 percentage predicted was 1.3% (0.1-2.4) predicted higher in 2020 for children 6 to <12 years of age, and 7.5% (7.1-7.9) predicted higher in 2020 among pwCF ⩾12 years of age eligible for the highly effective CF transmembrane conductance regulator modulator, elexacaftor-tezacaftor-ivacaftor (ETI). There was no difference in FEV1 percentage predicted for pwCF ⩾12 years of age who were not eligible for ETI. Similarly, the mean (95% CI) BMI was 2.4 (2.0-2.8) percentile higher in 2020 for children 6 to <12 years of age and 5.2 (4.8-5.7) percentile higher in 2020 among children 12 to <18 years of age eligible for ETI. Mean (95% CI) BMI was 1.2 (1.2-1.3) (kg/m2) higher for pwCF ⩾18 years of age eligible for ETI, and 0.2 (0.1-0.3) (kg/m2) higher for pwCF ⩾18 years of age not eligible for ETI. The proportion of in-person clinic visits where any PEx was present was lower in 2020 compared with 2019, 25% compared with 38%, RR 0.82 (0.79-0.86). Conclusions: The care of pwCF was substantially changed during the spring 2020 peak of the COVID-19 pandemic. Among pwCF seen in-person in both 2019 and 2020 after the spring peak of the COVID-19 pandemic, lung function and BMI were higher in 2020 for children 6 to <12 years of age and pwCF eligible for ETI.

Factors associated with clinical progression to severe COVID-19 in people with cystic fibrosis: A global observational study.

BACKGROUND: This international study aimed to characterise the impact of acute SARS-CoV-2 infection in people with cystic fibrosis and investigate factors associated with severe outcomes. Methods Data from 22 countries prior to 13th December 2020 and the introduction of vaccines were included. It was de-identified and included patient demographics, clinical characteristics, treatments, outcomes and sequalae following SARS-CoV-2 infection. Multivariable logistic regression was used to investigate factors associated with clinical progression to severe COVID-19, using the primary outcome of hospitalisation with supplemental oxygen. RESULTS: SARS-CoV-2 was reported in 1555 people with CF, 1452 were included in the analysis. One third were aged <18 years, and 9.4% were solid-organ transplant recipients. 74.5% were symptomatic and 22% were admitted to hospital. In the non-transplanted cohort, 39.5% of patients with ppFEV1<40% were hospitalised with oxygen verses 3.2% with ppFEV >70%: a 17-fold increase in odds. Worse outcomes were independently associated with older age, non-white race, underweight body mass index, and CF-related diabetes. Prescription of highly effective CFTR modulator therapies was associated with a significantly reduced odds of being hospitalised with oxygen (AOR 0.43 95%CI 0.31-0.60 p<0.001). Transplanted patients were hospitalised with supplemental oxygen therapy (21.9%) more often than non-transplanted (8.8%) and was independently associated with the primary outcome (Adjusted OR 2.45 95%CI 1.27-4.71 p=0.007). CONCLUSIONS: This is the first study to show that there is a protective effect from the use of CFTR modulator therapy and that people with CF from an ethnic minority are at more risk of severe infection with SARS-CoV-2.

Outcomes of infants born during the first 9 years of CF newborn screening in the United States: A retrospective Cystic Fibrosis Foundation Patient Registry cohort study.

INTRODUCTION: Newborn screening (NBS) for cystic fibrosis (CF) was implemented in all US states and DC by 2010. This hypothesis-generating study was designed to form the basis of additional analyses and to plan quality improvement initiatives. The aims were to describe the outcomes of infants with CF born during the first 9 years of universal NBS. METHODS: We included participants in the CF Foundation Patient Registry born 2010-2018 with age of recorded CF diagnosis 0-365 days old. We compared the age of center-reported diagnosis, age at first CF event (defined as earliest sweat test, clinic visit, or hospitalization), demographics, and outcomes between three cohorts born between 2010-2012, 2013-2015, and 2016-2018. RESULTS: In 6354 infants, the median age at first CF event decreased from the first to the third cohort. Weight-for-age (WFA) was < 10th percentile in about 40% of infants at the first CF Center visit. Median WFA z-score at 1-2 years was more than 0 but height-for-age (HFA) z-score was less than 0 through age 5-6 years. The second cohort had a higher HFA z-score than the first cohort at age 5-6 years. Pseudomonas aeruginosa infection was less common in later cohorts. About 1/3 of infants were hospitalized in the first year of life with no changes over time. CONCLUSION: Over 9 years of CF NBS, median age at first CF event decreased. CF NBS had positive health impacts, but early life nutritional deficits and a high rate of infant hospitalizations persist.

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.

Clinical characteristics of SARS-CoV-2 infection in children with cystic fibrosis: An international observational study.

BACKGROUND: The presence of co-morbidities, including underlying respiratory problems, has been identified as a risk factor for severe COVID-19 disease. Information on the clinical course of SARS-CoV-2 infection in children with cystic fibrosis (CF) is limited, yet vital to provide accurate advice for children with CF, their families, caregivers and clinical teams. METHODS: Cases of SARS-CoV-2 infection in children with CF aged less than 18 years were collated by the CF Registry Global Harmonization Group across 13 countries between 1 February and 7 August 2020. RESULTS: Data on 105 children were collated and analysed. Median age of cases was ten years (interquartile range 6-15), 54% were male and median percentage predicted forced expiratory volume in one second was 94% (interquartile range 79-104). The majority (71%) of children were managed in the community during their COVID-19 illness. Out of 24 children admitted to hospital, six required supplementary oxygen and two non-invasive ventilation. Around half were prescribed antibiotics, five children received antiviral treatments, four azithromycin and one additional corticosteroids. Children that were hospitalised had lower lung function and reduced body mass index Z-scores. One child died six weeks after testing positive for SARS-CoV-2 following a deterioration that was not attributed to COVID-19 disease. CONCLUSIONS: SARS-CoV-2 infection in children with CF is usually associated with a mild illness in those who do not have pre-existing severe lung disease.

Quantity not sufficient rates and delays in sweat testing in US infants with cystic fibrosis.

BACKGROUND: Diagnostic sweat testing is required for infants with positive newborn-screening (NBS) tests for cystic fibrosis (CF). Infants have "quantity not sufficient" (QNS) sweat volumes more often than older children. A comprehensive study of QNS sweat volumes in infants has not previously been reported. METHODS: We surveyed US CF Centers to obtain QNS rates in all infants who had sweat testing at under 14 days and under 3 months of age. We then calculated QNS rates reported to the Cystic Fibrosis Foundation Patient Registry (CFFPR) 2010-2018 in 10-day increments from 1 to 60 days of life. We compared QNS sweat test rates in preterm (<37-weeks gestational age) vs term infants. We assessed age at sweat test and proportion of infants who did not have a sweat test reported by 60 days of age. RESULTS: Thirty-nine of 144 (27%) of CF Centers reported a mean QNS rate of 10.5% (range, 0-100) in infants 14-days-old or younger. CFFPR data showed the highest QNS rates in the youngest infants and in those born before 37 weeks of gestation. The median age at sweat testing decreased over time, but more than 22% of infants did not have a sweat test reported by 60 days. CONCLUSION: Higher QNS rates are seen in the youngest infants with CF, but more than 80% of infants younger than 2 weeks of age have adequate sweat volumes. Sweat testing should not be delayed in infants with a positive CF NBS test.