Pancreatic Sufficiency Research Articles

Benign and Deleterious Cystic Fibrosis Transmembrane Conductance Regulator Mutations Identified by Sequencing in Positive Cystic Fibrosis Newborn Screen Children from California.

BackgroundOf the 2007 Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) mutations, 202 have been assigned disease liability. California’s racially diverse population, along with CFTR sequencing as part of newborn screening model, provides the opportunity to examine the phenotypes of children with uncategorized mutations to help inform disease liability and penetrance.MethodsWe conducted a retrospective cohort study based on children screened from 2007 to 2011 and followed for two to six years. Newborns that screened positive were divided into three genotype groups: those with two CF-causing mutations (CF-C); those with one mutation of varying clinic consequence (VCC); and those with one mutation of unknown disease liability (Unknown). Sweat chloride tests, pancreatic sufficiency status, and Pseudomonas aeruginosa colonization were compared.ResultsChildren with two CF-causing mutations had a classical CF phenotype, while 5% of VCC (4/78) and 11% of Unknown (27/244) met diagnostic criteria of CF. Children carrying Unknown mutations 2215insG with D836Y, and T1036N had early and classical CF phenotype, while others carrying 1525-42G>A, L320V, L967S, R170H, and 296+28A>G had a benign clinical presentation, suggesting that these are non-CF causing.ConclusionsWhile most infants with VCC and Unknown CFTR mutations do not meet diagnostic criteria for CF, a small proportion do. These findings highlight the range of genotypes and phenotypes in the first few years of life following CF newborn screening when CFTR sequencing is performed.

Pubertal Height Growth and Adult Height in Cystic Fibrosis After Newborn Screening.

To examine long-term growth benefit of newborn screening (NBS), adolescent peak height velocity (PHV), and adult height were compared between the screened (diagnosed early via NBS) and the control (identified generally by symptoms) in the Wisconsin Randomized Clinical Trial. Data from 107 children born in 1985-1994 and followed through 2012 were analyzed. PHV was estimated by a semiparametric growth curve model and compared with Tanner reference. Meconium ileus (MI; n = 25) was associated with the worst pubertal growth and adult height, including 1 child who did not experience apparent PHV; children with pancreatic sufficiency (n = 18) achieved the best growth (normal PHV and adult height). In children with pancreatic insufficiency without meconium ileus (n = 64), the subgroup most likely to benefit from NBS, screened children had similar PHV but better adult height compared with controls. Specifically, in boys, the screened group (n = 22) achieved normal PHV (9.5 cm at 13.5 years); the control group (n = 19) had similar onset age (13.6 years) but 0.6-cm lower magnitude (P = .08). In girls, the screened group (n = 10) had somewhat later (12.5 years vs 11.7 years, P = .12) and lower PHV (7.3 cm vs 7.9 cm, P = .33) than the controls (n = 13), coinciding with later menarche (13.6 years vs 12.2 years, P = .10). Adult height was taller in the screened than the control (50th vs 29th percentile, P = .02), even after adjusted for genetic potential (32nd vs15th percentile, P = .006). Differences in adult height were primarily attributable to NBS and better prepubertal growth. Early linear growth benefits of NBS were sustained through puberty, leading to better adult height in cystic fibrosis.

CFTR and/or pancreatitis susceptibility genes mutations as risk factors of pancreatitis in cystic fibrosis patients?

Background/objectivesCurrently, factors that promote the occurrence of pancreatitis episodes in patients affected with cystic fibrosis (CF) and pancreatic sufficiency (PS) are largely unknown. MethodsSix genes involved in pancreatitis or in ion transport into the pancreatic duct were investigated by next generation sequencing in 59 adult CF-PS patients with two identified CF mutations. Data on predisposing environmental factors were also recorded. Results19 experienced at least one episode of acute pancreatitis (AP) (AP+) and 40 patients did not (AP−). No influence of environmental factor was evidenced. No specific CFTR genotype was found predictive of pancreatitis. Patients sharing the same CFTR genotype may or may not experience AP episodes. Frequent and rare missense variants were found in 78.9% patients in group AP+ and 67.5% in group AP− but a few of them were pathogenic. ConclusionsAP or recurrent AP (RAP) is a frequent complication in our series of adult CF-PS patients. The majority of mild CFTR mutations found in group AP+ were located in the first transmembrane region. No clear other genetic factor could be found predictive of AP/RAP. Further experiments in large homogenous cohorts of CF-PS patients, including whole genome sequencing, may identify genetic predisposing factors to pancreatitis.

Refining the continuum of CFTR-associated disorders in the era of newborn screening.

Clinical heterogeneity in cystic fibrosis (CF) often causes diagnostic uncertainty in infants without symptoms and in older patients with milder phenotypes. We performed a cross-sectional evaluation of a comprehensive set of clinical and laboratory descriptors in a physician-defined cohort (N = 376; Children's Hospital of Wisconsin and the American Family Children's Hospital CF centers in Milwaukee and Madison, WI, USA) to determine the robustness of categorizing CF (N = 300), cystic fibrosis transmembrane conductance regulator (CFTR)-related disorder (N = 19), and CFTR-related (CRMS) metabolic syndrome (N = 57) according to current consensus guidelines. Outcome measures included patient demographics, clinical measures, sweat chloride levels, CFTR genotype, age at diagnosis, airway microbiology, pancreatic function, infection, and nutritional status. The CF cohort had a significantly higher median sweat chloride level (105 mmol/l) than CFTR-related disorder patients (43 mmol/l) and CFTR-related metabolic syndrome patients (35 mmol/l; p ≤ 0.001). Patient groups significantly differed in pancreatic sufficiency, immunoreactive trypsinogen levels, sweat chloride values, genotype, and positive Pseudomonas aeruginosa cultures (p ≤ 0.001). An automated classification algorithm using recursive partitioning demonstrated concordance between physician diagnoses and consensus guidelines. Our analysis suggests that integrating clinical information with sweat chloride levels, CFTR genotype, and pancreatic sufficiency provides a context for continued longitudinal monitoring of patients for personalized and effective treatment.

Nutritional status of adolescents with cystic fibrosis treated at a reference center in the southeast region of Brazil.

BackgroundSeveral factors can interfere with the full physical and emotional growth of adolescents, among them chronic diseases. The aim was to determine the nutritional status of adolescents and to associate it with puberty, pancreatic sufficiency, lung function and age range of Cystic Fibrosis (CF) diagnosis.MethodsAn observational, cross-sectional, retrospective and analytical study was conducted using the data of medical records. Setting: Reference center in the northeastern region of the state of São Paulo – Brazil. Patients: All adolescents with CF attended in 2010 were included. Some variables included: pancreatic sufficiency (steatocrit >2 %), pancreatic enzymes replacement (yes/no), pubertal status-Tanner criteria (prepubertal: M1/G1, pubertal: M2/G2 to M4/G4, postpubertal: M5/G5), age at CF diagnosis (<2 and ≥2 years of age), Lung function, measured as a predicted forced expiratory volume in 1 s (FEV1). Main outcome measures Nutritional indicators: body mass index for age (BMI/A) and height for age (H/A) with z-score calculated with Anthro Plus software. Cut-off reference points: ≥ z-score −3 and < z-score −2 (thinness); z-score −2 and ≤ z-score-z +1 (normal weight); >z-score +1 (overweight or obesity), and z-score <−2 (low or very low H/A). The groups were compared by the Kruskal-Wallis test. Level of significance: p < 0.05.ResultsThirty adolescents. Median (min;max) age: 14.4 (10.1;19.8) years. BMI/A and H/A z-score, respectively: early diagnosis of CF (−0.8; −1.1) or late diagnosis of CF (−0.5;-0.8); with pancreatic insufficiency (−0.7; −0.8) or without pancreatic insufficiency (−0.8; −0.5) and prepubertal (−0.8; −0.7) pubertal (−0.2; −1.5) or postpubertal (−0.7; -0.5). No significant difference (p > 0.05) was observed. Patients with and without pancreatic insufficiency, presented H/A borderline z-score (p = 0.05). Association between H/A and FEV1 was borderline (p = 0.05).ConclusionsAdolescents presented adequate nutritional status, although with slightly lower values than those of developed countries. FEV1 lower levels occurred more frequently in adolescents with low H/A.

PWE-212 Genotype-phenotype correlations in cystic fibrosis patients with pancreatitis highlights an increased likelihood of pancreatic insufficiency and identifies unique mutation pairs that potentially predispose to and protect from pancreatitis

Introduction 1–2% of cystic fibrosis (CF) patients develop symptomatic pancreatitis. Studies have shown these patients present later in life, are pancreatic sufficient (PS) and have a less severe CF phenotype. This study aimed to evaluate the genotype:phenotype relationship of CF patients with pancreatitis in a tertiary referral centre for CF. Method CF patients with a history of pancreatitis were identified from 1216 patients in The Royal Brompton Hospital CF database. Each case was age and sex matched with controls. Clinical information on age, sex, PS status, age when CF diagnosed, CF genotype and mortality were collected. To compare pancreatitis patients with controls, a two tailed t-test (age of CF diagnosis, R117H mutation rate) and Kaplan-Meir survival curves (rate of PI and mortality rates) were utilised. Results 37 patients (51% females) with pancreatitis were matched to 135 controls (3:1/4:1). Mean age of CF diagnosis was significantly higher in the pancreatitis group (19yrs) than controls (10.6yrs; p = 0.046). Median time between CF diagnosis and pancreatitis was 17 yrs (range 8–36 yrs). 65% (n = 24) of pancreatitis sufferers were PS at presentation to adult services; of these 63% (n = 15) remained PS until their most recent review or death. Furthermore, 67% (n = 16) suffered with recurrent or chronic pancreatitis. Using Log-rank (Mantal-Cox), there was no difference in survival between pancreatitis patients and controls (p = 0.97). However, pancreatitis patients were significantly more likely to develop PI (p = 0.012). The ^F508:R117H mutation pair was noted more frequently in pancreatitis patients (18.9%;n = 7) than controls (3.8%;n = 5) but not significancantly so (p = 0.56). Interestingly in 43% (n = 16) of the remaining pancreatitis patients, 15 mutation pairs unique to this group were identified. Similarly in controls, 50% (n = 65) had mutation pairs unique to this group. Conclusion CF patients who suffer with pancreatitis are significantly more likely to develop PI than those who do not. They present with CF at an older age but this does not affect their survival. The R117H mutation is seen more frequently in the pancreatitis group but not significantly so for this phenotype. We have identified a number of mutation pairs that seem to either predispose or protect CF patients from pancreatitis. Disclosure of interest None Declared.

210 Response to vitamin D supplementation protocol in CF pediatric patients

Objectives Previous study of 196 pediatric CF patients (pts) done at CHU Ste-Justine CF Clinic revealed that 2% of all pts had serum 25-hydroxyvitamin D (25(OH)D) deficiency ( 1 year received additional 1000 IU vitamin D, for a total of 1800 IU daily. Those who did not reach optimal levels received additional 10000 IU vitamin D once a week. The objective of this study is to document change in 25(OH)D levels in CF pediatric pts following our new protocol established in may 2012. Methods Retrospective chart review of vitamin D supplementation and 25(OH)D levels of 137 pts (126 pancreatic-insufficient (PI) and 11 pancreatic-sufficient (PS)) one year after protocol introduction. Results Serum 25(OH)D results from 2013 are presented. 61.3% of all pts had optimal 25(OH)D levels (PI = 62.7%, PS=45%), 38.7% had low levels (PI = 37.3%, PS=54%) and none had a deficiency. Mean vitamin D supplementation increased from 780 to 1614 IU daily and mean 25(OH)D levels increased from 67.6 to 82.4 nmol/L. 75.9% of all pts received 1800 IU daily, as per protocol. 66.3% of those patients had optimal 25(OH)D levels. Mean daily vitamin D supplementation of PS pts was 455 IU and their mean 25(OH)D level was 71 nmol/L. Conclusion Our protocol from may 2012 was followed for the majority of pts and resulted in an important increase of optimal 25(OH)D levels. We now have no vitamin D deficient pts (

10 Mild cystic fibrosis phenotype in adult patients with novel 3272–16T>A mutation

Objective Patients who have milder symptoms or atypical cystic fibrosis (CF) may have at least one so called class V mutation. This class includes mutations that leave residual levels of normal CFTR transcripts and protein. Recently by sequencing of the coding region of the CFTR gene and exon-intron junctions we've revealed 3272–16T>A mutation in Russian adult CF patients. As far as we know this mutation hasn't been described (before December 2014) by any other geneticists and it is not in the CFTR1 and CFTR2 lists. 3272–16T>A mutation is a splicing mutation in intron 19 of CFTR gene (thymine to adenine substitution). Aim To reveal the clinical characteristics of 3272–16T>A mutation in CF adult patients. Methods Adult CF patients carrying 3272–16T>A mutation were included in the study. The following data were evaluated: the age at CF diagnosis, pancreatic status, the presence of the following complications: meconium ileus or DIOS, diabetes and liver cirrhosis. Results We've found 10 patients (6 men) carried 3272–16T>A mutation and the following mutations in the other CFTR allele: F508del – 6 patients, 394delTT – 2 patients, 2184insA – 1 patient, not identified – 1 patient. The average age of patients was 27.4±5.5 years (from 18.4 to 35.0 years). Age at diagnosis ranged from 3.5 to 26.9 years (12.3±7.0 yrs). All 10 were pancreatic sufficient. None of them had meconium ileus in anamnesis or DIOS, diabetes and liver cirrhosis. Conclusion 3272–16T>A mutation is a mild mutation associated with pancreatic sufficiency and lack of development of some complications specific to the classical CF genotypes.

WS18.2 Using funnel plots to make meaningful centre comparisons

Objectives The UK CF Registry annual reports include comparisons between centres on key outcomes such as FEV 1 using rankings. While illustrating the distribution between centres, they promote the assumption that those with the highest measures provide better care. We hypothesised a more scientific approach based on statistical process control and adjustment for case-mix may identify exceptional CF care services in terms of clinically meaningful outcomes. Methods We extracted FEV 1 and BMI on patients aged 12–21 from annual review data (2007–2012). Funnel plots were generated with confidence limits at 2 and 3 standard deviations (SD). Centres with mean values outside these limits are said to display cause – variability outside what one would expect. Outcomes were then adjusted for case mix (including gender, genotype, pancreatic sufficiency and socio-economic deprivation) and analysed using funnel plots. Results Using a primary outcome of FEV 1 at age 15, data for 1066 patients from 31 paediatric centres were available. Funnel plots of unadjusted data showed 8 centres with evidence of special cause variation (at 2SD limits). Initial adjustment for case-mix reduced the number of centres outside these limits to 3. None of the centres were outside the 3SD limits in either analysis. Similar patterns were found for BMI percentile in this age group. Conclusion In conclusion the work to-date illustrates that funnel plots can be used to identify differences in FEV 1 and BMI between specialist paediatric centres. Case-mix adjustment models should develop into a useful tool for making centre comparisons which can continue to be used by stakeholders.

WS18.4 Five-year survivorship in cystic fibrosis: Outcomes improve but the disease remains the same

Objectives Investigate the stability of the five-year survival model in Liou et al (Am J Epidemiol, 153:345, 2001). Methods After obtaining IRB approval, we analyzed data from the CFFPR from 1993–2010, breaking patients into three non-overlapping cohorts starting in 1993, 1999, and 2005, and following for five years, excluding transplanted patients. For each cohort, we developed a five-year survivorship model with logistic regression (glm function in R) and compared with the published model, using covariates: age, FEV1% predicted, weight-for-age z-score, sex, Burkholderia complex, pancreatic sufficiency, methicillin-sensitive Staphylococcus aureus, CF-related diabetes, and number of acute pulmonary exacerbations in the prior year. Results The five-year survival predictions from the three new models closely match those of the original model (1993 cohort, R2 = 0.98, 1999 cohort, R2 = 0.93, 2005 cohort, R2 = 0.99). Compared with the 1993 cohort, mortality in later cohorts is reduced (OR 0.81 in 1999 and 0.64 in 2005). The distribution of probabilities of death in five years based on the original model differ between eras (p Conclusion From 1993 to 2009, the factors predicting mortality in CF have remained stable. The dramatic reduction in mortality during the study period results from the improvement in clinical measurements, implying that the progression of the disease has slowed even though survivorship from a given disease state remains unchanged.

Clinical and demographic factors associated with post–lung transplantation survival in individuals with cystic fibrosis

Contemporary studies evaluating post-transplant survival are limited and often include data from single centers or selected sub-groups. The purpose of this study was to evaluate overall transplant survival and to identify risk factors associated with death after transplant. The Canadian Cystic Fibrosis Registry, a population-based cohort, was used to describe survival after lung transplant. Pre-transplant factors associated with post-transplant survival were estimated using Cox proportional hazards models. Between 1988 and 2012, 580 patients received a lung transplant. In the entire cohort, post-lung transplant 1-year survival was 87.8%, 5-year survival was 66.7%, and 10-year survival was 50.2%. Median post-transplant survival was 3.3 years (95% confidence interval [CI] = 2.13-6.56) in patients infected with Burkholderia cepacia complex compared with 12.36 years (95% CI = 10.34-17.96) in patients without B cepacia infection (hazard ratio [HR] = 2.63, 95% CI = 2.0-3.44). After adjustment, there was a non-significant trend toward better post-transplant survival with increasing year of transplant (HR = 0.98, 95% CI = 0.96-1.00). Pancreatic sufficiency (HR = 2.13, 95% CI = 1.41-3.20) and age at transplant such that youngest and oldest had the poorest survival (p < 0.001) were significant negative predictors of survival. The risk of death after transplant for patients infected with B cepacia was highest within the first year (HR = 6.29, 95% CI = 3.87-10.21) but remained elevated >1 year after transplant (HR = 1.92, 95% CI = 1.33-2.77) compared with patients without B cepacia infection. After lung transplantation, 5-year survival in Canadians with CF is 67%, and 50% of patients live >10 years. Despite these impressive probabilities, age at transplant, pancreatic sufficiency and B cepacia infection remain important determinants of survival after lung transplantation.

Multidimensional clinical phenotyping of an adult cystic fibrosis patient population.

BackgroundCystic Fibrosis (CF) is a multi-systemic disease resulting from mutations in the Cystic Fibrosis Transmembrane Regulator (CFTR) gene and has major manifestations in the sino-pulmonary, and gastro-intestinal tracts. Clinical phenotypes were generated using 26 common clinical variables to generate classes that overlapped quantiles of lung function and were based on multiple aspects of CF systemic disease.MethodsThe variables included age, gender, CFTR mutations, FEV1% predicted, FVC% predicted, height, weight, Brasfield chest xray score, pancreatic sufficiency status and clinical microbiology results. Complete datasets were compiled on 211 subjects. Phenotypes were identified using a proximity matrix generated by the unsupervised Random Forests algorithm and subsequent clustering by the Partitioning around Medoids (PAM) algorithm. The final phenotypic classes were then characterized and compared to a similar dataset obtained three years earlier.FindingsClinical phenotypes were identified using a clustering strategy that generated four and five phenotypes. Each strategy identified 1) a low lung health scores phenotype, 2) a younger, well-nourished, male-dominated class, 3) various high lung health score phenotypes that varied in terms of age, gender and nutritional status. This multidimensional clinical phenotyping strategy identified classes with expected microbiology results and low risk clinical phenotypes with pancreatic sufficiency.InterpretationThis study demonstrated regional adult CF clinical phenotypes using non-parametric, continuous, ordinal and categorical data with a minimal amount of subjective data to identify clinically relevant phenotypes. These studies identified the relative stability of the phenotypes, demonstrated specific phenotypes consistent with published findings and identified others needing further study.

Insulin secretion abnormalities in exocrine pancreatic sufficient cystic fibrosis patients

BackgroundThe aim of this study is to assess insulin secretion in pediatric cystic fibrosis (CF) patients with exocrine pancreatic sufficiency. MethodsGlucose and insulin responses during an oral glucose tolerance test (OGTT) were measured in 146 CF patients. Patients were divided into exocrine sufficient (CF-PS) and insufficient (CF-PI) groups based on pancreatic enzyme usage and fecal elastase. A reference group included healthy, non-diabetic subjects. ResultsAll CF groups showed reduced insulin secretion as measured by insulinogenic index. The CF-PS patients had normal glucose tolerance. There was a direct correlation between BMI z-score and insulin area under the curve. ConclusionPatients with CF have reduced insulin secretion during an OGTT regardless of exocrine pancreatic status. The abnormal insulin secretion in all CF patients may predispose them for glucose intolerance, particularly when challenged by inflammation, infection, or nutritional deficiency. In addition, the diminished insulin secretion may contribute to increased catabolism. Lastly, the CF-related diabetes (CFRD) screening guidelines should be followed by all CF patients regardless of pancreatic status.

Association between serum 25-hydroxyvitamin D level and pulmonary exacerbations in cystic fibrosis.

To identify effects of vitamin D status, as defined by circulating 25-hydroxyvitamin D (25-OHD) levels on the annual frequency of pulmonary exacerbations (Pex) and hospitalizations, on standard measures of pulmonary function, and to identify determinants of 25-OHD levels in pediatric patients with cystic fibrosis (CF). Higher levels of serum 25-OHD would be associated with fewer Pex and hospitalizations, and improved lung function based on pulmonary function tests (PFTs). Retrospective chart review of 53 pediatric patients from January 2011 to December 2011. Significant relationships were examined using linear and logistic regression analyses. Patients ages 5 through 22 years followed at the CF Care Center and Clinic at Yale-New Haven Hospital, New Haven, CT., who had at least four clinic visits and at least one 25-OHD measurement between January 1, 2011 and December 31, 2011. Serum 25-OHD level and gender were strong independent determinants of the annual number of Pex (P < 0.01, with lower 25-OHD level and female gender associated with Pex). There was a significant influence of gender (P < 0.05) and a near-significant influence of serum 25-OHD (P < 0.08) on hospitalization rate. There was no effect of 25-OHD levels on PFTs. Other candidate factors (age, season, gender, pancreatic sufficiency, or severity of genetic mutation) did not significantly effect 25-OHD level. The annual number of Pex in pediatric CF patients is significantly associated with 25-OHD levels and gender, raising the consideration that maintaining vitamin D sufficiency may lead to decreased incidence of Pex and hospitalizations requiring antibiotic therapy.

223 Analysis of “cost drivers” for health care services use in cystic fibrosis patients: the experience of the Milan Cystic Fibrosis Center

Objectives: To identify and model − from the perspective of the NHS − the main “cost drivers” for health care use in CF patients, to facilitate a more rational management of resources and a better understanding of the economic impact of the introduction of new treatments. Methods: The dataset used for this study was the one collected by Colombo et al. [Adv Ther s 12325-013-0008-5 (2013)], which includes 165 consecutive patients seen during the period March–July 2009 at the CF center of Milano (Lombardy) and followed for one year. Nineteen anamnestic and treatment related parameters were tested as explanatory variables for the total yearly cost(s) of the patient borne by the NHS. The analysis was performed by means of multivariate LS regression. Results: The best fitting model (r2 = 0.73; adjusted r2 = 0.71) was as follows: Log(total cost) = 9.485 − 0.657·(pancreatic sufficiency) − 0.013·FEV1 + 0.950·(use of dornase) + 0.931·(use of inhalatory antibiotic maintenance treatment) + 0.029·(age at diagnosis) − 0.377·(meconium ileus). The p value for the intercept and the first 4 parameters was <0.0004, for the last two was <0.07. Conclusion: Some of the findings are essentially in line with what was previously reported by similar studies, even though the impact of dornase on the cost seems less relevant (r2 = 0.64 without dornase). Other parameters (such as for example gender, BMI, age, age at diagnosis and a positive history for meconium ileus), which in the studied population seem to have a different relevance, warrant further analysis and investigations.

206 Serum zinc concentration in cystic fibrosis patients with CFTR I1234V mutation associated with pancreatic sufficiency

206 Serum zinc concentration in cystic fibrosis patients with CFTR I1234V mutation associated with pancreatic sufficiency

Differences in Disease Expression Between Primary Ciliary Dyskinesia and Cystic Fibrosis With and Without Pancreatic Insufficiency

Impaired mucociliary clearance causes pulmonary disease in primary ciliary dyskinesia (PCD) and contributes to cystic fibrosis (CF) lung disease. Although the sinopulmonary disease is similar, morbidity and mortality are different. Both patients with PCD and patients with CF with pancreatic sufficiency (CF-PS) show no nutrient malabsorption and are diagnosed at a later age compared with patients with CF with pancreatic insufficiency (CF-PI). Clinical status, microbiology, FEV1, and high-resolution CT (HRCT) scans presented as total Brody score (CT-TBS) were compared for patients with PCD, CF-PI, and CF-PS, all treated at the same medical center, by the same team, and by a similar routine follow-up. One hundred sixty-four patients, 34 with PCD, 88 with CF-PI, and 42 with CF-PS were enrolled. PCD was diagnosed at a similar age as CF-PS but significantly later than CF-PI. Mean FEV1 % predicted was similar for the three groups. The rate of FEV1 change with age in PCD was similar to CF-PS but significantly lower than in CF-PI. Severity of structural lung disease (CT-TBS) was similar for PCD and CF-PS and significantly higher in CF-PI. No correlation between TBS or Pseudomonas aeruginosa infection and FEV1 in PCD was seen, whereas a negative correlation with FEV1 was observed for both CF groups. Although in our study PCD was similar to CF-PS, the lack of correlation between FEV1 and age, CT-TBS, and P aeruginosa infection in PCD suggests that impaired mucociliary clearance is not the only cause for inducing pulmonary damage in these diseases. Furthermore, a comparison of disease characteristics for PCD and CF should distinguish between CF-PI and CF-PS as different entities.

Gastrointestinal Pathology in Juvenile and Adult CFTR-Knockout Ferrets

Cystic fibrosis (CF) is a multiorgan disease caused by loss of a functional cystic fibrosis transmembrane conductance regulator (CFTR) chloride channel in many epithelia of the body. Here we report the pathology observed in the gastrointestinal organs of juvenile to adult CFTR-knockout ferrets. CF gastrointestinal manifestations included gastric ulceration, intestinal bacterial overgrowth with villous atrophy, and rectal prolapse. Metagenomic phylogenetic analysis of fecal microbiota by deep sequencing revealed considerable genotype-independent microbial diversity between animals, with the majority of taxa overlapping between CF and non-CF pairs. CF hepatic manifestations were variable, but included steatosis, necrosis, biliary hyperplasia, and biliary fibrosis. Gallbladder cystic mucosal hyperplasia was commonly found in 67% of CF animals. The majority of CF animals (85%) had pancreatic abnormalities, including extensive fibrosis, loss of exocrine pancreas, and islet disorganization. Interestingly, 2 of 13 CF animals retained predominantly normal pancreatic histology (84% to 94%) at time of death. Fecal elastase-1 levels from these CF animals were similar to non-CF controls, whereas all other CF animals evaluated were pancreatic insufficient (<2 μg elastase-1 per gram of feces). These findings suggest that genetic factors likely influence the extent of exocrine pancreas disease in CF ferrets and have implications for the etiology of pancreatic sufficiency in CF patients. In summary, these studies demonstrate that the CF ferret model develops gastrointestinal pathology similar to CF patients.

Prediction of acute pancreatitis risk based on PIP score in children with cystic fibrosis

BackgroundCurrently no tools to predict risk of acute (AP) and recurrent pancreatitis (ARP) in children with cystic fibrosis (CF) are available. We assessed the prevalence of AP/ARP and tested the potential role of Pancreatic Insufficiency Prevalence (PIP) score in a cohort of children with CF. MethodsWe identified two groups of children, on the basis of presence/absence of AP/ARP, who were compared for age at diagnosis, clinical features, genotypes and sweat chloride level. PIP score was calculated for each patient. Results10/167 (5.9%) experienced at least one episode of AP during follow up; 10/10 were pancreatic sufficient (PS). Patients with AP/ARP showed a PIP score ≤0.25 more frequently (6/10) than patients without AP/ARP. The odds ratio (95% CI) of developing pancreatitis was 4.54 (1.22–16.92) for patients with PIP <0.25 when compared with those who have a PIP score >0.25 (p 0.0151). PIP score was correlated with sweat chloride test (p<0.01). ConclusionPIP score, PS status and normal/borderline sweat chloride levels could be applied to predict pancreatitis development in children with CF. ARP could lead to pancreatic insufficiency.

Bone Mineral Density in Cystic Fibrosis Patients with the CFTR I1234V Mutation in a Large Kindred Family Is Associated with Pancreatic Sufficiency.

Objectives. To study bone mineral density (BMD) in cystic fibrosis (CF) children and adults with the CFTR I1234V mutation associated with pancreatic sufficiency. Methods. Lumbar spine, total hip, and whole-body mineral density were measured by dual-energy radiographic absorptiometry (DEXA) scan. Z score was used for those less than 21 years and T score was used for those 21 years or older. Results. Twenty-one CF patients were younger than 21 years and 5 CF patients were 21 years or older. Mean age was 17.29 ± 4.95 years, ranging from 10 to 33 years. The mean BMD Z scores for patients younger than 21 years were −0.69 ± 0.96 (lumbar spine = L1–L4), −0.48 ± 0.92 (total hip), and −0.38 ± 0.86 (total body). The mean T scores for patients 21 years or older were 0.14 ± 0.7 (L1–L4), 0.38 ± 1 (total hip), and 0.52 ± 1.03 (total body). BMD reduction less than −1 was found in 7 (26.9%) CF patients. Vitamin D deficiency in 20 CF patients (76.9%) tended to be lower in CF patients with low BMD. BMD was significantly correlated with FEV1; however, no significant association was observed with P. aeruginosa colonization. Conclusion. BMD reduction does occur in patients with mild CFTR mutation associated with pancreatic sufficiency.