Impact of Discontinuing Both Hypertonic Saline and Dornase Alfa After Elexacaftor/Tezacaftor/Ivacaftor in Cystic Fibrosis.

Rationale Evaluating approaches to reduce treatment burden is a research priority among people with CF (pwCF) on highly effective modulators including elexacaftor/tezacaftor/ivacaftor (ETI). Objective To evaluate the impact of discontinuing both hypertonic saline (HS) and dornase alfa (DA) versus continuing both therapies among a subgroup of participants in the SIMPLIFY study who sequentially participated in trials evaluating the independent clinical effects of discontinuing HS and DA. Methods SIMPLIFY participants ≥12 years old on ETI and comprising a subgroup using both HS and DA at study entry were randomized to the HS or DA trial, and then randomized 1:1 to continue or discontinue the applicable therapy for 6 weeks. After completion of the first trial, eligible participants could enroll in the second trial beginning with a 2-week run in. Study outcomes were compared across the duration of SIMPLIFY participation between a cohort remaining on both therapies during SIMPLIFY versus a cohort that sequentially discontinued both as a result of trial randomizations. Multivariable regression models were used to estimate treatment differences, adjusted for time between trials, trial order, baseline age, sex at birth and percent predicted forced expiratory volume in one second (ppFEV1) at study entry. Results There were 43 participants who discontinued both therapies by the end of SIMPLIFY and 63 who remained on both, with overall average ppFEV1 at study entry 96.7% and average duration of follow up from beginning of the first trial to completion of the second trial 3.9 months, including time between trials. No clinically meaningful difference in the change in ppFEV1 from baseline to completion of the second trial was observed between those who discontinued versus remained on both therapies (difference: 0.22% Off-On, 95% CI: -1.60,2.03). Changes in LCI2.5, patient reported, and safety outcomes were also comparable. Patient reported treatment burden, as measured by a CFQ-R subscale, significantly decreased in those discontinuing both therapies. Conclusions SIMPLIFY participants who sequentially discontinued both HS and DA experienced no meaningful changes in clinical outcomes and reported decreased treatment burden as compared to those who remained on both therapies. These data continue to inform a new era of post-modulator care of pwCF.

Vitamin D status and variable responses to supplements depend in part on genetic factors in adults with cystic fibrosis.

Vitamin D sufficiency has been difficult to achieve consistently in patients with cystic fibrosis (CF), even with robust oral supplements. To assess vitamin D status and resistance to supplementation, we studied 80 adults using 25-hydroxyvitamin D (25OHD) determinations and whole genome sequencing to construct polygenic risk scores (PRS) that aggregate variants associated with vitamin D status. The results revealed that 30 % of patients were below the threshold of 30 ng/mL and thus should be regarded as insufficient despite normal vitamin E status, a reflection of adherence to fat soluble vitamin supplementation. The PRS values were significantly correlated with 25OHD concentrations, confirming our results in children with CF, and indicating that genetic factors play a role and have implications for therapy.

Using A Work System Framework to Investigate Pharmacists' Roles in Cystic Fibrosis Management.

OBJECTIVE: Cystic fibrosis (CF) is a genetic disease that requires complex, lifelong treatment regimens to maintain health and reduce disease progression. The aims of this study were 1) to gain the perspectives of multiple health professions to understand medication and well-being challenges of people living with CF; and 2) to apply the Systems Engineering Initiative for Patient Safety (SEIPS) model to further identify opportunities for pharmacists to support people with CF. METHODS: Health care professionals were recruited from a Cystic Fibrosis Center in the Midwest, to participate in audio-recorded semistructured interviews. Topics examined during the interviews included medication education for patients as well as experiences with outpatient, specialty, and community pharmacists. The themes assessed during the pharmacist interviews included support for people living with CF, preferences in conducting medication education, and pharmacist-specific counseling. Interview transcripts were thematically analyzed into categories to determine major themes. Prevalent codes were categorized into 5 major themes guided by the SEIPS model. Interrater reliability was strong (kappa = 0.94). RESULTS: Five major themes were identified: 1) patient tasks; 2) external environment; 3) organizational conditions; 4) patient medication education; and 5) pharmacists' roles and tasks. Professionals identified the importance of the pharmacist on the multidisciplinary CF care team to enhance patient-centered care for people living with CF. CONCLUSIONS: This study highlights health care professionals' views on the unique skillset that pharmacists add to the care team, including a reduction in medication errors, improved adherence, and overall enhanced patient care.

Newborn screening alone insufficient to improve pulmonary outcomes for cystic fibrosis.

BACKGROUND: The Wisconsin Cystic Fibrosis Neonatal Screening Project was a randomized clinical trial (RCT) revealing that children receiving an early diagnosis of CF via newborn screening (NBS) had improved nutritional outcomes but similar lung disease severity compared to those who presented clinically. Because the evaluations of these subjects by protocol ended in 2012, our objective was to assess long-term pulmonary and mortality outcomes. METHODS: Retrospective analysis of the RCT cohort utilized longitudinal outcome measures obtained from the Cystic Fibrosis Foundation Patient Registry (CFFPR). Data included screening assignment, clinical characteristics, percent predicted forced expiratory volume in 1 s (ppFEV1) and mortality. A random intercept model was used to compare the ppFEV1 decline of subjects between the two groups up to age 26 years. Mortality was analyzed using the Kaplan-Meier method. RESULTS: Of the 145 subjects who consented to the original study, 104 subjects met inclusion criteria and had adequate data in the CFFPR. Of 57 subjects in the screened group and 47 in the control group, the rates of ppFEV1 decline were 1.76%/year (95% CI 1.62 to 1.91%) and 1.43%/year (95% CI 1.26 to 1.60%), respectively (p<0.0002). Pseudomonas aeruginosa acquired before 2 years was partially responsible. There was no difference in mortality between the two groups. CONCLUSIONS: NBS alone does not improve pulmonary outcomes in CF, particularly when other risk factors supervene. In an era prior to strict infection control and current therapies, NBS for CF may be associated with worse pulmonary outcomes.

Applying whole-genome sequencing in relation to phenotype and outcomes in siblings with cystic fibrosis.

Variations in disease onset and/or severity have often been observed in siblings with cystic fibrosis (CF), despite the same CFTR genotype and environment. We postulated that genomic variation (modifier and/or pharmacogenomic variants) might explain these clinical discordances. From a cohort of patients included in the Wisconsin randomized clinical trial (RCT) of newborn screening (NBS) for CF, we identified two brothers who showed discordant lung disease courses as children, with one milder and the other more severe than average, and a third, eldest brother, who also has severe lung disease. Leukocytes were harvested as the source of DNA, and whole-genome sequencing (WGS) was performed. Variants were identified and analyzed using in-house-developed informatics tools. Lung disease onset and severity were quantitatively different between brothers during childhood. The youngest, less severely affected brother is homozygous for HFE p.H63D. He also has a very rare PLG p.D238N variant that may influence host-pathogen interaction during chronic lung infection. Other variants of interest were found differentially between the siblings. Pharmacogenomics findings were consistent with the middle, most severely affected brother having poor outcomes to common CF treatments. We conclude that genomic variation between siblings with CF is expected. Variable lung disease severity may be associated with differences acting as genetic modifiers and/or pharmacogenomic factors, but large cohort studies are needed to assess this hypothesis.

Polysomnographic Markers in Children With Cystic Fibrosis Lung Disease.

BACKGROUND AND OBJECTIVES: Children with cystic fibrosis (CF) often report poor sleep, increased daytime sleepiness, and fatigue. The purpose of this study was to identify respiratory patterns over the spectrum of disease severity in children with CF. The overall hypothesis for the current study is that children with CF compared with snoring control subjects demonstrate gas exchange abnormalities and increased respiratory loads during sleep that are not reported or recognized by conventional polysomnography (PSG). METHODS: Analysis of breathing patterns and gas exchange on PSG was performed in children with CF and healthy controls matched by age and BMI. For all CF and control subjects, the indication for PSG was evaluation for obstructive sleep apnea based on a history of snoring. RESULTS: Children with CF, compared with age- and BMI-matched snoring controls, demonstrated lower oxyhemoglobin saturation (95% ± 1.6% vs 98% ± 0.6%, P = .005), higher respiratory rate (19.5 ± 4.9 vs 16.5 ± 1.2 breaths per minute, P = .03), and a higher proportion of inspiratory flow limitation (44.1% ± 24.7% vs 12.1% ± 13.5%, P = .007) during non-rapid eye movement sleep. The respiratory disturbance index did not differ between CF and snoring control groups (1.5 ± 2.7 vs 0.6 ± 0.6 events per hour, P = .11). CONCLUSIONS: Children with CF exhibited abnormalities in gas exchange and increased respiratory load during sleep compared with normal age- and BMI-matched snoring controls. Because these abnormalities were independent of weight and lung function, sleep state may serve as an opportunity for early detection of breathing abnormalities and possibly CF lung disease progression.

Impact of lung allocation score on survival in cystic fibrosis lung transplant recipients.

BACKGROUND: The lung allocation score (LAS) has changed organ allocation for lung transplantation in the United States. Previous investigations of transplant recipients reported an association between high LAS and an increased risk of death after lung transplantation. We hypothesize that a high LAS predicts survival in lung transplant recipients with cystic fibrosis (CF) in the United Network for Organ Sharing Scientific Registry of Transplant Recipients database. METHODS: A cohort study was conducted of 1,437 U.S. adult lung transplant recipients with CF from May 1, 2005, through December 31, 2012. The cohort was divided into a high-risk group and a low-risk group based on LAS. Survival data were examined using Kaplan-Meier estimates and Cox proportional hazard models to compare survival. The primary outcome was adjusted survival at 1 year after lung transplantation. RESULTS: The high-risk group of 318 patients with a median LAS of 69.6 (interquartile range 56.3-87.2) was compared with a low-risk group of 1,119 patients with a median LAS of 38.8 (interquartile range 36.3-42.3). Patients in the high-risk group had a 41% increased relative risk of cumulative mortality at 1 year after transplantation compared with the low-risk group (16.1% vs 12.0%). After adjustment for known predictors of mortality, the risk of death at 1 year after transplantation remained elevated (hazard ratio = 1.41; 95% confidence interval = 1.00-2.01). The high-risk group had worse survival at 90 days and 2 years after lung transplantation. CONCLUSIONS: High LAS are associated with worse survival in lung transplant recipients with CF.

Cystic fibrosis lung transplantation.

PURPOSE OF REVIEW: This review summarizes recently published investigations on issues pertaining to cystic fibrosis (CF) lung transplantation. We specifically focus on indications and candidate selection as well as infectious and noninfectious issues specific to CF lung transplant recipients. RECENT FINDINGS: Recent studies have focused on candidate adequacy in high-risk CF patients. We review the current literature on individuals who develop respiratory failure requiring mechanical ventilation and those patients with a pretransplant diagnosis of pulmonary hypertension. Furthermore, the management of peri-operative infectious issues is reviewed including recurrent infections with multidrug-resistant bacterial, mycobacterial, and fungal organisms. Other CF-specific issues addressed include common comorbidities such as CF-related diabetes, gastroesophageal reflux, CF liver disease, and bone metabolism. SUMMARY: Lung transplantation is a limited, but potentially life-saving therapeutic option for patients with CF. Optimal candidate selection and awareness of CF-specific issues in the pretransplant and posttransplant setting may lead to better long-term outcomes.

Cystic fibrosis mutations and genotype-pulmonary phenotype analysis.

BACKGROUND: Although there are more than 1000 mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene, most of them are uncommon and only limited information exists regarding genotype-pulmonary phenotype relationships. METHODS: We determined and classified the CFTR mutations using denaturing high-performance liquid chromatography and developed new, quantitative methods to categorize pulmonary phenotypes. RESULTS: Two novel alleles were discovered, namely G1047R and 1525-2A-->G, which were accompanied by F508del and G551D mutations, respectively. Assessment of numerous options revealed that CF pulmonary phenotype categorization in children cannot be accomplished with clinical or pulmonary function data but is facilitated by longitudinal quantitative chest radiology. It was most useful to categorize pulmonary disease status by evaluating the typical pattern of abnormalities in patients homozygous for the F508del mutation, and then compare patients with minor mutations to this typical CF pulmonary phenotype. By this method, both patients with novel mutations have pulmonary phenotypes typical of F508del homozygotes. However, patients with class IV mutations (e.g., R347P) or with pancreatic sufficiency showed serial chest radiographs that were atypically mild. CONCLUSIONS: Longitudinal quantitative chest radiography provides a new strategy for CF pulmonary phenotype categorization that should be useful for genotype-phenotype delineation in individual patients and in both epidemiologic studies and clinical trials involving groups of children with CF.