Predicting lung function decline in cystic fibrosis: the impact of initiating ivacaftor therapy.

BACKGROUND: Modulator therapies that seek to correct the underlying defect in cystic fibrosis (CF) have revolutionized the clinical landscape. Given the heterogeneous nature of lung disease progression in the post-modulator era, there is a need to develop prediction models that are robust to modulator uptake. METHODS: We conducted a retrospective longitudinal cohort study of the CF Foundation Patient Registry (N = 867 patients carrying the G551D mutation who were treated with ivacaftor from 2003 to 2018). The primary outcome was lung function (percent predicted forced expiratory volume in 1 s or FEV1pp). To characterize the association between ivacaftor initiation and lung function, we developed a dynamic prediction model through covariate selection of demographic and clinical characteristics. The ability of the selected model to predict a decline in lung function, clinically known as an FEV1-indicated exacerbation signal (FIES), was evaluated both at the population level and individual level. RESULTS: Based on the final model, the estimated improvement in FEV1pp after ivacaftor initiation was 4.89% predicted (95% confidence interval [CI]: 3.90 to 5.89). The rate of decline was reduced with ivacaftor initiation by 0.14% predicted/year (95% CI: 0.01 to 0.27). More frequent outpatient visits prior to study entry and being male corresponded to a higher overall FEV1pp. Pancreatic insufficiency, older age at study entry, a history of more frequent pulmonary exacerbations, lung infections, CF-related diabetes, and use of Medicaid insurance corresponded to lower FEV1pp. The model had excellent predictive accuracy for FIES events with an area under the receiver operating characteristic curve of 0.83 (95% CI: 0.83 to 0.84) for the independent testing cohort and 0.90 (95% CI: 0.89 to 0.90) for 6-month forecasting with the masked cohort. The root-mean-square errors of the FEV1pp predictions for these cohorts were 7.31% and 6.78% predicted, respectively, with standard deviations of 0.29 and 0.20. The predictive accuracy was robust across different covariate specifications. CONCLUSIONS: The methods and applications of dynamic prediction models developed using data prior to modulator uptake have the potential to inform post-modulator projections of lung function and enhance clinical surveillance in the new era of CF care.

Reduction of Recurrence Risk of Pancreatitis in Cystic Fibrosis With Ivacaftor: Case Series.

The effect of ivacaftor in patients with cystic fibrosis (CF) with recurrent pancreatitis is unknown. We conducted a multicenter retrospective study of patients with CF taking ivacaftor who had a history of recurrent pancreatitis. During the first 3 months of therapy, only 1 of the 6 patients had an episode of pancreatitis, which was managed on an outpatient basis. Between 3 and 12 months on ivacaftor therapy, none of the patients had recurrence of pancreatitis or required hospitalization. The use of ivacaftor was associated with a reduced frequency and recurrence rate of pancreatitis in patients with CF.

Electronic monitoring reveals highly variable adherence patterns in patients prescribed ivacaftor.

BACKGROUND: Previous studies of CF treatments have shown suboptimal adherence, though little has been reported regarding adherence patterns to ivacaftor. Electronic monitoring (EM) of adherence is considered a gold standard of measurement. METHODS: Adherence rates by EM were prospectively obtained and patterns over time were analyzed. EM-derived adherence rates were compared to pharmacy refill history and self-report. RESULTS: 12 subjects (age 6-48 years; CFTR-G551D mutation) previously prescribed ivacaftor were monitored for a mean of 118 days. Overall adherence by EM was 61% (SD=28%) and decreased over time. Median duration between doses was 16.9 hours (IQR 13.9-24.1 hours) and increased over time. There was no correlation between EM-derived adherence and either refill history (84%, r=0.26, p=0.42) or self-report (100%, r=0.40, p=0.22). CONCLUSIONS: Despite the promising nature of ivacaftor, our data suggest adherence rates are suboptimal and comparable to other prescribed CF therapies, and more commonly used assessments of adherence may be unreliable.

Adherence Determinants in Cystic Fibrosis: Cluster Analysis of Parental Psychosocial, Religious, and/or Spiritual Factors.

RATIONALE: Cystic fibrosis is a progressive disease requiring a complex, time-consuming treatment regimen. Nonadherence may contribute to an acceleration of the disease process. Spirituality influences some parental healthcare behaviors and medical decision-making. OBJECTIVES: We hypothesized that parents of children with cystic fibrosis, when classified into groups based on adherence rates, would share certain psychosocial and religious and/or spiritual variables distinguishing them from other adherence groups. METHODS: We conducted a multisite, prospective, observational study focused on parents of children younger than 13 years old at two cystic fibrosis center sites (Site 1, n= 83; Site 2, n = 59). Religious and/or spiritual constructs, depression, and marital adjustment were measured by using previously validated questionnaires. Determinants of adherence included parental attitude toward treatment, perceived behavioral norms, motivation, and self-efficacy. Adherence patterns were measured with the Daily Phone Diary, a validated instrument used to collect adherence data. Cluster analysis identified discrete adherence patterns, including parents' completion of more treatments than prescribed. MEASUREMENTS AND MAIN RESULTS: For airway clearance therapy, four adherence groups were identified: median adherence rates of 23%, 52%, 77%, and 120%. These four groups differed significantly for parental depression, sanctification of their child's body, and self-efficacy. Three adherence groups were identified for nebulized medications: median adherence rates of 35%, 82%, and 130%. These three groups differed significantly for sanctification of their child's body and self-efficacy. CONCLUSIONS: Our results indicated that parents in each group shared psychosocial and religious and/or spiritual factors that differentiated them. Therefore, conversations about adherence likely should be tailored to baseline adherence patterns. Development of efficacious religious and/or spiritual interventions that promote adherence by caregivers of children with cystic fibrosis may be useful.

The impact of transforming healthcare delivery on cystic fibrosis outcomes: a decade of quality improvement at Cincinnati Children's Hospital.

BACKGROUND: In 2001, Cincinnati Children's Hospital embarked on a journey to improve healthcare delivery to patients with cystic fibrosis (CF). Data from the Cystic Fibrosis Foundation National Patient Registry revealed our below-average clinical outcomes, prompting us to initiate improvement interventions. OBJECTIVE: To improve clinical outcomes for patients with CF through a comprehensive quality-improvement approach directed at increasing patient centredness and improving healthcare delivery. INTERVENTIONS: In 2001, we shared our below-average outcomes with patients, families and care providers. We instituted a quality-improvement steering committee with parental and hospital leadership, and our data-management support was restructured to provide real-time clinical data to monitor our progress. In 2002, our weekly chart conference changed to a prospective planning session and individualised daily schedules were created for inpatients. In 2003, an influenza vaccination campaign was initiated and our infection-control practices were redesigned. In 2005, best-practice guidelines were developed for airway-clearance therapy. In 2007, evidence-based clinical algorithms were designed and implemented and key care-team members were added. MEASUREMENTS: Primary outcome measures were median forced expiratory volume in 1 s per cent predicted (age range 6-17 years) and median body mass index percentile (age range 2-20 years). RESULTS: From 2000 to 2010, median forced expiratory volume in 1 s increased from 81.7% to 100.1% predicted and median body mass index increased from the 35th to the 55th centile. DISCUSSION: By focusing on specific outcomes, empowering families and patients, effectively using data, and standardising care processes, we transformed the culture and delivery of care for our patients with CF and learned valuable lessons potentially translatable to other chronic-care providers.