Correlating Cystic Fibrosis Transmembrane Conductance Regulator Function with Clinical Features to Inform Precision Treatment of Cystic Fibrosis.

Rationale: The advent of precision treatment for cystic fibrosis using small-molecule therapeutics has created a need to estimate potential clinical improvements attributable to increases in cystic fibrosis transmembrane conductance regulator (CFTR) function. Objectives: To derive CFTR function of a variety of CFTR genotypes and correlate with key clinical features (sweat chloride concentration, pancreatic exocrine status, and lung function) to develop benchmarks for assessing response to CFTR modulators. Methods: CFTR function assigned to 226 unique CFTR genotypes was correlated with the clinical data of 54,671 individuals enrolled in the Clinical and Functional Translation of CFTR (CFTR2) project. Cross-sectional FEV1% predicted measurements were plotted by age at which measurement was obtained. Shifts in sweat chloride concentration and lung function reported in CFTR modulator trials were compared with function-phenotype correlations to assess potential efficacy of therapies. Measurements and Main Results: CFTR genotype function exhibited a logarithmic relationship with each clinical feature. Modest increases in CFTR function related to differing genotypes were associated with clinically relevant improvements in cross-sectional FEV1% predicted over a range of ages (6-82 yr). Therapeutic responses to modulators corresponded closely to predictions from the CFTR2-derived relationship between CFTR genotype function and phenotype. Conclusions: Increasing CFTR function in individuals with severe disease will have a proportionally greater effect on outcomes than similar increases in CFTR function in individuals with mild disease and should reverse a substantial fraction of the disease process. This study provides reference standards for clinical outcomes that may be achieved by increasing CFTR function.

Reference percentiles of FEV1 for the Canadian cystic fibrosis population: comparisons across time and countries.

BACKGROUND: Forced expiratory volume in 1 s (FEV1) indicates lung health in cystic fibrosis (CF). FEV1 is commonly communicated as a per cent predicted of a healthy individual sharing the same age, sex, race and height. CF-specific reference equations are complementary and calibrate a patient's FEV1 to that of their CF peers. OBJECTIVES: (1) To derive Canadian CF-specific FEV1 reference percentiles (FEV1%iles), (2) characterize how they have changed over time and (3) compare the Canadian FEV1%iles to those for USA and European CF populations. METHOD: CF FEV1%iles are calculated using the Canadian CF Registry and quantile regression. RESULTS: The Canadian FEV1%iles demonstrated better lung function in more recent time periods within Canada, especially below the 50% percentile and in males. When compared to USA and European FEV1%iles for the same time period, Canadian FEV1%iles were higher. CONCLUSION: CF-specific FEV1%iles can provide useful information about changes in lung health. An online calculator (available at cfpercentile. RESEARCH: sickkids.ca) makes these FEV1%iles accessible.

Does extensive genotyping and nasal potential difference testing clarify the diagnosis of cystic fibrosis among patients with single-organ manifestations of cystic fibrosis?

BACKGROUND: The phenotypic spectrum of cystic fibrosis (CF) has expanded to include patients affected by single-organ diseases. Extensive genotyping and nasal potential difference (NPD) testing have been proposed to assist in the diagnosis of CF when sweat testing is inconclusive. However, the diagnostic yield of extensive genotyping and NPD and the concordance between NPD and the sweat test have not been carefully evaluated. METHODS: We evaluated the diagnostic outcomes of genotyping (with 122 mutations included as disease causing), sweat testing and NPD in a prospectively ascertained cohort of undiagnosed patients who presented with chronic sino-pulmonary disease (RESP), chronic/recurrent pancreatitis (PANC) or obstructive azoospermia (AZOOSP). RESULTS: 202 patients (68 RESP, 42 PANC and 92 AZOOSP) were evaluated; 17.3%, 22.8% and 59.9% had abnormal, borderline and normal sweat chloride results, respectively. Only 17 (8.4%) patients were diagnosable as having CF by genotyping. Compared to sweat testing, NPD identified more patients as having CF (33.2%) with fewer borderline results (18.8%). The level of agreement according to kappa statistics (and the observed percentage of agreement) between sweat chloride and NPD in RESP, PANC and AZOOSP subjects was 'moderate' (65% observed agreement), 'poor' (33% observed agreement) and 'fair' (28% observed agreement), respectively. The degree of agreement only improved marginally when subjects with borderline sweat chloride results were excluded from the analysis. CONCLUSIONS: The diagnosis of CF or its exclusion is not always straightforward and may remain elusive even with comprehensive evaluation, particularly among individuals who present at an older age with single-organ manifestations suggestive of CF.

Longitudinal relationship between physical activity and lung health in patients with cystic fibrosis.

Exercise is beneficial for patients with cystic fibrosis (CF) but long-term effects of physical activity on lung function evolution are unknown. We evaluated the longitudinal relationship between changes in habitual physical activity (HPA) and rate of decline in lung function in patients with CF. We tracked HPA using the Habitual Activity Estimation Scale, forced expiratory volume in 1 s (FEV1) and Stage I exercise tests in 212 patients with CF over a 9-year period. Adjusting for sex, baseline age and FEV1, mucoid Pseudomonas aeruginosa and CF-related diabetes, mean ± sd FEV1 % predicted decreased by 1.63 ± 0.08% per year (p<0.0001) while mean ± sd HPA increased by 0.28 ± 0.03 h·day(-1) per year (p<0.0001) over the study period. A greater increase in HPA was associated with a slower rate of decline in FEV1 (r=0.19, p<0.0069). Dividing subjects into "high" and "low" activity (above or below the mean rate of change of activity, respectively), a steeper rate of FEV1 decline was observed for low (-1.90% per year) compared to high (-1.39% per year) (p=0.002). Increases in HPA are feasible despite progression of lung disease and are associated with a slower rate of decline in FEV1, highlighting the benefit of regular physical activity, and its positive impact on lung function in patients with CF.

Home-based rehabilitation enhances daily physical activity and motor skill in children who have undergone the Fontan procedure.

This randomized trial compared physical activity enhancing exercise prescription and education programs in 61 children (36 male) with single-ventricle physiology after Fontan. After Fontan, children are less active than recommended for optimal health. They are often geographically dispersed and unable to attend weekday programs. Participants, 5.9-11.7 years of age who were status 5.3 years post-Fontan, received 12-month, parent-delivered home programs to enhance physical activity, motor skill, fitness, and activity attitudes. Daily moderate-to-vigorous physical activity (MVPA) was measured at baseline and again at 6, 12, and 24 months. Secondary outcomes were gross motor skill, fitness, and activity attitudes. Gross motor skill (p = .01) was significantly greater at the end of the 2-year study period for both intervention groups combined. MVPA at 2 years was significantly greater (p = .03) than the predicted decrease with age. Spring season (85 ± 25 min), male sex (69 ± 21 min), greater baseline activity (0.3 ± 0.1 min/baseline minute), and better gross motor skill (1.1 ± 0.4 min/percentile) increased weekly MVPA in a multivariable repeated-measures regression model adjusted for intervention, maturation during the 2-year study, sex, season, and baseline activity. Benefits were not influenced by type of rehabilitation, compliance, or rural/urban location. Home-based, pediatric physical activity rehabilitation enhances physical activity, gross motor skill, exercise capacity, and physical fitness among preadolescent children after Fontan regardless of rural/urban location. Prescribed education and exercise programs are similarly effective for providing the important health benefits of daily physical activity. Enhanced gross motor skill is associated with increased MVPA despite exercise capacity limitations after Fontan. Rehabilitation attenuates the expected decrease in MVPA with age.

Type of CFTR mutation determines risk of pancreatitis in patients with cystic fibrosis.

BACKGROUND & AIMS: Different mutations in the cystic fibrosis gene (CFTR) are associated with different functional status of the exocrine pancreas. We investigated whether CFTR genotypes determine the risk of pancreatitis in patients with cystic fibrosis (CF). METHODS: Patients with pancreatic-sufficient CF were identified from 2 CF population-based databases (N = 277; 62 with pancreatitis and 215 without pancreatitis); patients' genotypes and clinical characteristics were analyzed. The loss of pancreatic function associated with each CFTR genotype was determined based on the pancreatic insufficiency prevalence (PIP) score. RESULTS: Patients with pancreatitis were more likely to have genotypes associated with mild (70%) than moderate-severe (30%) PIP scores (P = .004). The cumulative proportion of patients who developed pancreatitis through to the age of 50 years was significantly greater for genotypes associated with mild (50%) than moderate-severe (27%) PIP scores (P = .006). The genotype associated with mild PIP scores had a hazard ratio of 2.4 for pancreatitis (95% confidence interval, 1.3-4.5; P = .006). Patients with pancreatitis were diagnosed with CF at an older median age than those without pancreatitis (14.9 years [interquartile range, 9.5-27.7] vs 9.3 years [interquartile range, 1.5-21.4]; P = .003) and had lower mean levels of sweat chloride than patients without pancreatitis (74.5 ± 26.2 mmol/L vs 82.8 ± 25.2 mmol/L; P = .03). CONCLUSIONS: Specific CFTR genotypes are significantly associated with pancreatitis. Patients with genotypes associated with mild phenotypic effects have a greater risk of developing pancreatitis than patients with genotypes associated with moderate-severe phenotypes. This observation provides further insight into the complex pathogenesis of pancreatitis.

TLR5 as an anti-inflammatory target and modifier gene in cystic fibrosis.

New treatments are needed to improve the health of people with cystic fibrosis (CF). Reducing lung-damaging inflammation is likely to be beneficial, but specific anti-inflammatory targets have not been identified. By combining cellular immunology with a population-based genetic modifier study, we examined TLR5 as an anti-inflammatory target and modifier gene in CF. Using two pairs of human CF and control airway epithelial cells, we demonstrated that the TLR5-flagellin interaction is a major mediator of inflammation following exposure to Pseudomonas aeruginosa. To validate TLR5 as an anti-inflammatory target, we analyzed the disease modifying effects of the TLR5 c.1174C>T single nucleotide polymorphism (rs5744168) in a large cohort of CF patients (n = 2219). rs5744168 encodes a premature stop codon and the T allele is associated with a 45.5-76.3% reduction in flagellin responsiveness (p < 0.0001). To test the hypothesis that reduced TLR5 responsiveness would be associated with improved health in CF patients, we examined the relationship between rs5744168 and two clinical phenotypes: lung function and body weight. Adults with CF carrying the TLR5 premature stop codon (CT or TT genotype) had a higher body mass index than did CF patients homozygous for the fully functional allele (CC genotype) (p = 0.044); however, similar improvements in lung function associated with the T allele were not statistically significant. Although follow-up studies are needed to confirm the impact of TLR5 on nutritional status, this translational research provides evidence that genetic variation in TLR5 resulting in reduced flagellin responsiveness is associated with improved health indicators in adults with CF.

Caution advised in the use of CFTR modulator treatment for individuals harboring specific CFTR variants.

In December 2020, the U.S. Food and Drug Administration (FDA) expanded the list of CFTR variants approved for treatment with CFTR modulators drugs from 39 to 183. Clinicians should be aware that individuals harboring certain variants approved for treatment may not respond to or benefit from this therapy. After review, the expert panel leading the CFTR2 project identified four categories of variants that may not result in a clinical response to modulator treatment: 15 variants assigned as non CF-causing; 45 variants of unknown significance; six variants known or suspected to cause mis-splicing as their primary defect rather than an amino acid substitution; and eight variants known to occur together in cis with another deleterious variant not expected to lead to CFTR protein (nonsense or frameshift). The potential risks and benefits of CFTR modulator therapy should be considered carefully for individuals harboring these variants.

Complex two-gene modulation of lung disease severity in children with cystic fibrosis.

Although cystic fibrosis (CF) is a monogenic disease, its clinical manifestations are influenced in a complex manner. Severity of lung disease, the main cause of mortality among CF patients, is likely modulated by several genes. The mannose-binding lectin 2 (MBL2) gene encodes an innate immune response protein and has been implicated as a pulmonary modifier in CF. However, reports have been conflicting, and interactions with other modifiers have not been investigated. We therefore evaluated the association of MBL2 with CF pulmonary phenotype in a cohort of 1,019 Canadian pediatric CF patients. MBL2 genotypes were combined into low-, intermediate-, and high-expression groups based on MBL2 levels in plasma. Analysis of age at first infection with Pseudomonas aeruginosa demonstrated that MBL2 deficiency was significantly associated with earlier onset of infection. This MBL2 effect was amplified in patients with high-producing genotypes of transforming growth factor beta 1 (TGFB1). Similarly, MBL2 deficiency was associated with more rapid decline of pulmonary function, most significantly in those carrying the high-producing TGFB1 genotype. These findings provide evidence of gene-gene interaction in the pathogenesis of CF lung disease, whereby high TGF-beta1 production enhances the modulatory effect of MBL2 on the age of first bacterial infection and the rate of decline of pulmonary function.

Factors associated with the physical activity level of children who have the Fontan procedure.

BACKGROUND: Children with complex heart defects are sedentary, with activity level unrelated to exercise capacity. We sought to identify factors associated with physical activity level for children who have the Fontan procedure. METHODS: We used a cross-sectional study, 64 children (25 female, 5-11 years) after Fontan. Measurements were weekly minutes of moderate-to-vigorous physical activity, cardiac status, resting/exercise cardiopulmonary capacity, gross motor skill, health-related endurance/strength/body composition, and parent/child activity perceptions. RESULTS: Participants performed 361 ± 137 minutes per week of moderate-to-vigorous physical activity. Increased activity related to antithrombotic medication use (86 min/wk), lower resting heart rate (3 min/wk), higher weekday outdoor time (0.7 minutes per outside minute), lower family income (13 minutes per $10,000), and higher parent rating of child's activity relative to peers (36 min/wk). Factors related to decreased activity were winter season (-84 min/wk), history of arrhythmia (-96 min/wk), and greater child confidence in own ability to be active (-113 min/wk). CONCLUSIONS: Physical activity after the Fontan procedure is primarily associated with factors unrelated to cardiac status. Interventions that impact these modifiable factors would be expected to enable these children to achieve the recommended activity levels associated with optimal health.

Interactions with Home and Health Environments Discourage Physical Activity: Reports from Children with Complex Congenital Heart Disease and Their Parents.

Children with complex congenital heart disease are less active than recommended for optimal health, with social and physical environments important determinants. The purpose of this study was to examine the physical activity perceptions of children with complex congenital heart disease and their parents to identify social and physical environment intervention targets. A semi-structured discussion guide elicited physical activity perceptions from children (26 boys, 19 girls, 6.0-12.4 years) with complex congenital heart disease (single ventricle n = 42) and their parents during three child and three parent focus groups and 41 interviews. Interviews and focus groups were audio-recorded and transcribed verbatim for inductive thematic analysis. Children and parents identified home, peer and health environments as impacting on their children's physical activity participation. Peer environments, such as school or daycare, were supportive by providing physical activity facilities and enabling fun with peers and time outdoors. At home, parent and sibling interactions both encouraged and discouraged physical activity. The children's unique health environment fostered physical activity uncertainty, discouraging activity despite minimal or no physician recommendations to restrict physical activity. Children with complex congenital heart disease and their parents recognize the importance of physical activity and fun with friends. Physical activity uncertainty contributes to their inactive lifestyles despite minimal restrictions from health professionals. Positive clinical encouragement and health environment interventions that better support physical activity are required.

Modifier gene study of meconium ileus in cystic fibrosis: statistical considerations and gene mapping results.

Cystic fibrosis (CF) is a monogenic disease due to mutations in the CFTR gene. Yet, variability in CF disease presentation is presumed to be affected by modifier genes, such as those recently demonstrated for the pulmonary aspect. Here, we conduct a modifier gene study for meconium ileus (MI), an intestinal obstruction that occurs in 16-20% of CF newborns, providing linkage and association results from large family and case-control samples. Linkage analysis of modifier traits is different than linkage analysis of primary traits on which a sample was ascertained. Here, we articulate a source of confounding unique to modifier gene studies and provide an example of how one might overcome the confounding in the context of linkage studies. Our linkage analysis provided evidence of a MI locus on chromosome 12p13.3, which was segregating in up to 80% of MI families with at least one affected offspring (HLOD = 2.9). Fine mapping of the 12p13.3 region in a large case-control sample of pancreatic insufficient Canadian CF patients with and without MI pointed to the involvement of ADIPOR2 in MI (p = 0.002). This marker was substantially out of Hardy-Weinberg equilibrium in the cases only, and provided evidence of a cohort effect. The association with rs9300298 in the ADIPOR2 gene at the 12p13.3 locus was replicated in an independent sample of CF families. A protective locus, using the phenotype of no-MI, mapped to 4q13.3 (HLOD = 3.19), with substantial heterogeneity. A candidate gene in the region, SLC4A4, provided preliminary evidence of association (p = 0.002), warranting further follow-up studies. Our linkage approach was used to direct our fine-mapping studies, which uncovered two potential modifier genes worthy of follow-up.

Reference ranges for spirometry across all ages: a new approach.

RATIONALE: The Third National Health and Nutrition Examination Survey (NHANES III) reference is currently recommended for interpreting spirometry results, but it is limited by the lack of subjects younger than 8 years and does not continuously model spirometry across all ages. OBJECTIVES: By collating pediatric data from other large-population surveys, we have investigated ways of developing reference ranges that more accurately describe the relationship between spirometric lung function and height and age within the pediatric age range, and allow a seamless transition to adulthood. METHODS: Data were obtained from four surveys and included 3,598 subjects aged 4-80 years. The original analyses were sex specific and limited to non-Hispanic white subjects. An extension of the LMS (lambda, mu, sigma) method, widely used to construct growth reference charts, was applied. MEASUREMENTS AND MAIN RESULTS: The extended models have four important advantages over the original NHANES III analysis as follows: (1) they extend the reference data down to 4 years of age, (2) they incorporate the relationship between height and age in a way that is biologically plausible, (3) they provide smoothly changing curves to describe the transition between childhood and adulthood, and (4) they highlight the fact that the range of normal values is highly dependent on age. CONCLUSIONS: The modeling technique provides an elegant solution to a complex and longstanding problem. Furthermore, it provides a biologically plausible and statistically robust means of developing continuous reference ranges from early childhood to old age. These dynamic models provide a platform from which future studies can be developed to continue to improve the accuracy of reference data for pulmonary function tests.

Genetic modifiers of liver disease in cystic fibrosis.

CONTEXT: A subset (approximately 3%-5%) of patients with cystic fibrosis (CF) develops severe liver disease with portal hypertension. OBJECTIVE: To assess whether any of 9 polymorphisms in 5 candidate genes (alpha(1)-antitrypsin or alpha(1)-antiprotease [SERPINA1], angiotensin-converting enzyme [ACE], glutathione S-transferase [GSTP1], mannose-binding lectin 2 [MBL2], and transforming growth factor beta1 [TGFB1]) are associated with severe liver disease in patients with CF. DESIGN, SETTING, AND PARTICIPANTS: Two-stage case-control study enrolling patients with CF and severe liver disease with portal hypertension (CFLD) from 63 CF centers in the United States as well as 32 in Canada and 18 outside of North America, with the University of North Carolina at Chapel Hill as the coordinating site. In the initial study, 124 patients with CFLD (enrolled January 1999-December 2004) and 843 control patients without CFLD were studied by genotyping 9 polymorphisms in 5 genes previously studied as modifiers of liver disease in CF. In the second stage, the SERPINA1 Z allele and TGFB1 codon 10 genotype were tested in an additional 136 patients with CFLD (enrolled January 2005-February 2007) and 1088 with no CFLD. MAIN OUTCOME MEASURES: Differences in distribution of genotypes in patients with CFLD vs patients without CFLD. RESULTS: The initial study showed CFLD to be associated with the SERPINA1 Z allele (odds ratio [OR], 4.72; 95% confidence interval [CI], 2.31-9.61; P = 3.3 x 10(-6)) and with TGFB1 codon 10 CC genotype (OR, 1.53; 95% CI, 1.16-2.03; P = 2.8 x 10(-3)). In the replication study, CFLD was associated with the SERPINA1 Z allele (OR, 3.42; 95% CI, 1.54-7.59; P = 1.4 x 10(-3)) but not with TGFB1 codon 10. A combined analysis of the initial and replication studies by logistic regression showed CFLD to be associated with SERPINA1 Z allele (OR, 5.04; 95% CI, 2.88-8.83; P = 1.5 x 10(-8)). CONCLUSIONS: The SERPINA1 Z allele is a risk factor for liver disease in CF. Patients who carry the Z allele are at greater risk (OR, approximately 5) of developing severe liver disease with portal hypertension.

Genetic modifiers of lung disease in cystic fibrosis.

BACKGROUND: Polymorphisms in genes other than the cystic fibrosis transmembrane conductance regulator (CFTR) gene may modify the severity of pulmonary disease in patients with cystic fibrosis. METHODS: We performed two studies with different patient samples. We first tested 808 patients who were homozygous for the DeltaF508 mutation and were classified as having either severe or mild lung disease, as defined by the lowest or highest quartile of forced expiratory volume in one second (FEV1), respectively, for age. We genotyped 16 polymorphisms in 10 genes reported by others as modifiers of disease severity in cystic fibrosis and tested for an association in patients with severe disease (263 patients) or mild disease (545). In the replication (second) study, we tested 498 patients, with various CFTR genotypes and a range of FEV1 values, for an association of the TGFbeta1 codon 10 CC genotype with low FEV1. RESULTS: In the initial study, significant allelic and genotypic associations with phenotype were seen only for TGFbeta1 (the gene encoding transforming growth factor beta1), particularly the -509 and codon 10 polymorphisms (with P values obtained with the use of Fisher's exact test and logistic regression ranging from 0.006 to 0.0002). The odds ratio was about 2.2 for the highest-risk TGFbeta1 genotype (codon 10 CC) in association with the phenotype for severe lung disease. The replication study confirmed the association of the TGFbeta1 codon 10 CC genotype with more severe lung disease in comparisons with the use of dichotomized FEV1 for severity status (P=0.0002) and FEV1 values directly (P=0.02). CONCLUSIONS: Genetic variation in the 5' end of TGFbeta1 or a nearby upstream region modifies disease severity in cystic fibrosis.

An international/multicentre report on patients with cystic fibrosis (CF) over the age of 40 years.

BACKGROUND: The lifespan of patients with cystic fibrosis (CF) is increasing significantly. The objective of this international pilot study was to study the characteristics of these long-term survivors. METHODS: Four centres with large CF clinics from London (UK), Minneapolis (USA), Toronto (Canada) and Verona (Italy) identified 366 patients who had survived 40 years and longer. RESULTS: At all centres males survived longer than females. There were more pancreatic sufficient patients in Verona (60%) and Toronto (40%) than in London (16%) and Minneapolis (21%). The percentage of DeltaF508 homozygous patients varied between 47% in London and 45% in Minneapolis to only 26% in Toronto and 9% in Verona. Average FEV(1) and BMI values of the surviving population appeared to stabilise after 40 years of age. FEV(1) was on average 12% higher in patients who were pancreatic sufficient (p > 0.0001). There was no difference in survival between the centres. The overall median survival after the age of 40 was 13 years. The estimated annual death rate was approximately 3.4% from the age of 40-60 years. CONCLUSIONS: Significant numbers of patients are now surviving to 40 years or more, and it is hoped that an in-depth study of these patients may identify the factors contributing to longer survival.

Field testing of the 2006 World Health Organization growth charts from birth to 2 years: assessment of hospital undernutrition and overnutrition rates and the usefulness of BMI.

BACKGROUND: The World Health Organization (WHO) recently released a growth standard, a first attempt at describing how children should grow in an ideal environment. These charts introduce body mass index (BMI)-for-age percentiles for children younger than 2 years. Adopting the WHO standard may affect the number of children screened to require follow-up; hence, field testing needs to be completed in a tertiary care center where the incidence of suboptimal nutrition is high. The objectives of this study were to quantify differences between the new WHO and 2000 Centers for Disease Control and Prevention (CDC) growth charts for children younger than 2 years. The interchangeability of the WHO weight-for-length and WHO BMI percentiles was also assessed. METHODS: Percentile scores were computed for children younger than 2 years (n = 547) admitted to a pediatric tertiary health care center in Toronto, Canada. RESULTS: The WHO standard identified more children younger than 2 years as at risk of overweight/obesity compared with the CDC reference (21.0% vs 16.6%, >or=85th weight-for-length percentile) and fewer children as wasted (18.6% vs 23.0%, <5th weight-for-length percentile). The WHO BMI-for-age and WHO weight-for-length percentiles were highly correlated (r2 = 0.83) but not interchangeable. For approximately 9% of all children, and approximately 16% of those aged 25 percentile points. CONCLUSIONS: These data describe for the first time the magnitude of differences in the number of children screened as undernourished (4.4% decrease) or overnourished (4.4% increase) with adoption of the WHO standard in a tertiary care setting. Furthermore, the WHO's BMI-for-age and weight-for-length percentiles for children younger than 2 years are correlated but are not interchangeable.

Cholecalciferol significantly increases 25-hydroxyvitamin D concentrations in adults with cystic fibrosis.

BACKGROUND: Vitamin D deficiency is increasingly being recognized and treated in patients with cystic fibrosis, although the treatment guidelines are not proven and the effectiveness of vitamin D preparations is untested. OBJECTIVES: The aims of this study were to determine the prevalence of 25-hydroxyvitamin D [25(OH)D] deficiency in a large cohort of adults with cystic fibrosis and to evaluate the effectiveness of supplementation with cholecalciferol. DESIGN: In this retrospective cohort design, baseline 25(OH)D concentrations were measured, and the effects of clinical interventions that involved either counseling on compliance or increasing supplemental cholecalciferol on serum 25(OH)D concentrations in those subjects with baseline concentrations

High-dose ibuprofen in cystic fibrosis: Canadian safety and effectiveness trial.

OBJECTIVE: To assess the effectiveness and safety of high-dose ibuprofen when used as part of routine therapy in patients with cystic fibrosis (CF). STUDY DESIGN: In this multicenter, double-blinded, placebo-controlled trial, a total of 142 patients age 6 to 18 years with mild lung disease (forced expiratory volume in 1 minute [FEV1] > 60 predicted) were randomized to receive either high-dose ibuprofen (70 subjects, 20 to 30 mg/kg/twice daily, adjusted to a peak serum concentration of 50 to 100 mug/mL) or placebo (72 subjects) for a 2-year period. The primary outcome was the annualized rate of change in FEV1% predicted. RESULTS: The patients in the high-dose ibuprofen group exhibited a significant reduction in the rate of decline of forced vital capacity percent predicted (0.07 +/- 0.51 vs -1.62 +/- 0.52; P = .03), but not FEV1%. The ibuprofen group also spent fewer days in hospital after adjusting for age (1.8 vs 4.1 days per year; P = .07). A total of 11 patients (4 in the ibuprofen group and 7 in the placebo group) withdrew due to adverse events. CONCLUSIONS: High-dose ibuprofen has a significant effect on slowing the progression of lung disease in CF and generally is well tolerated.